Fused bicyclic ARYL compounds for boron neutron capture therapy

Abstract

Disclosed are compounds, compositions, and methods useful for boron neutron capture therapy.

Description

[0001] FUSED BICYCLIC ARYL COMPOUNDS FOR BORON NEUTRON CAPTURE THERAPY RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application serial number 63 / 605,920, filed December 4, 2023. BACKGROUND Boron neutron capture therapy (BNCT) is a bimodal cancer therapy that requires a boron- containing molecule that selectively partitions into cancer cells and an external neutron beam directed to the cancer. Capture of thermal neutrons by the10B nuclei inside the cancer cells results in nuclear fission to give high-energy alpha particles and recoiling7Li nuclei. The high- energy particles damage the tumor cells resulting in tumor cell death while sparing surrounding healHhy tissue. New boron delivery agents that selectively partition into tumor tissue in combination with an external neutron beam directed to the tumor may be useful in boron neutron capture therapy for the treatment of various solid tumors. 4-Borono-L-phenylalanine (BPA) is approved in Japan for use in combination with an external neutron beam device for the treatment of recurrent unresectable head & neck cancer. While BPA has demonstrated therapeutic utility in boron neutron capture therapy, it has limitations. Its selectivity for tumor tissue over healthy tissue and its tumor uptake are considered to meet only the minimal requirements for a successful boron neutron capture therapy agent. Agents that have improved uptake into tumor cells and have an improved tumor:healthy tissue ratio relative to BPA may result in improved anti-cancer efficacy. SUMMARY One aspect of the invention provides compounds, compositions, and methods useful for boron neutron capture therapy. Accordingly, provided herein is a compound having the structure of Formula (I): wherein A1is selected from –O– and –NH–; A2is selected from –C(O)–, –C(R5)(R6)–, and N; A3is a single bond, –C(R7)(R8)–, or –C(H)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R5, R6, R7, and R8are each independently selected from –H and alkyl; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; is a pi bond or absent; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof; provided that if is a pi bond, then A2is N and A3is –C(H)–; if A1is O; A2is CH2; A3is a single bond; and R3is –CH2C(H)(NH2)CO2H; then at least one of R1, R2, and R4is not H; and if A1is O; A2is CH2; A3is a single bond; and R1is -CH2C(H)(NH2)CO2H; then at least one of R2, R3, and R4is not H. Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof a compound of Formula (I) or pharmaceutical composition comprising a compound of Formula (I), wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. DETAILED DESCRIPTION Definitions For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon, or of a boron with10B-enriched boron, are within the scope of this invention. The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit / risk ratio applicable to any medical treatment. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30for straight chains, C3-C30for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen. As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl. As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene -(CH2CH2CH2)-, isopropylene - (CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. "Cycloheteroalkyl" refers to a cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and / or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6alkyl, C3-6cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da). In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. A series of treatments may comprise a second or subsequent treatment weeks to months after a first or preceding treatment. The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10- fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response. A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and / or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Compounds of the Invention One aspect of the invention relates to a compound of Formula (I): wherein A1 is selected from –O– and –NH–; A2is selected from –C(O)–, –C(R5)(R6)–, and N; A3is a single bond, –C(R7)(R8)–, or –C(H)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R5, R6, R7, and R8are each independently selected from –H and alkyl; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; is pi bond or absent; the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof; provided that if is a pi bond,2 3 then A is N and A is –C(H)–; if A1is O; A2is CH2; A3is a single bond; and R3is –CH2C(H)(NH2)CO2H; then at least one of R1, R2, and R4is not H; and if A1is O; A2is CH2; A3is a single bond; and R1is -CH2C(H)(NH2)CO2H; then at least one of R2, R3, and R4is not H. Another aspect of the invention relates to a compound of Formula (IA): wherein A1is selected from –O– and –NH–; A2 is selected from –C(O)– and –C(R5)(R6)–; A3is a single bond or –C(R7)(R8)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R5, R6, R7, and R8are each independently selected from –H and alkyl; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof; provided that if A1is O; A2is CH2; A3is a single bond; and R3is –CH2C(H)(NH2)CO2H; then at least one of R1, R2, and R4is not –H; and if A1is O; A2is CH2; A3is a single bond; and R1is -CH2C(H)(NH2)CO2H; then at least one of R2, R3, and R4is not –H. In certain embodiments, R2is –(CR'R'')nC(H)(NH2)CO2H; and R1, R3, and R4are each –H. In certain embodiments, R3is –(CR'R'')nC(H)(NH2)CO2H; and R1, R2, and R4are each – H. In certain embodiments, R4is –(CR'R'')nC(H)(NH2)CO2H; and R1, R2, and R3are each – H. In certain embodiments, each of R' and R'' –H. In certain embodiments, R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CH2)nC(H)(NH2)CO2H; In certain embodiments, one of R' and R'' is –H; and the other of R' and R'' is selected from halogen and alkyl. In certain embodiments, R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, and –(CHR'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CHR'')nC(H)(NH2)CO2H; and R'' is selected from halogen and alkyl. In certain embodiments, R1is not –(CR'R'')nC(H)(NH2)CO2H.In certain embodiments, n is 0. In other embodiments, n is 1. In certain embodiments, R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H. In certain embodiments, R1, R2, R3, and R4are each independently selected from –H, halogen, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H. In certain embodiments, halogen is –F. In certain embodiments, A1is selected from –O– and –NH–; A2is selected from –C(O)– and –C(R5)(R6)–; and A3is a single bond. In certain embodiments, n is 1. In certain embodiments, the compound having the structure: . In certain embodiments, the compound having the structure selected from: , , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: and , wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: , and ; wherein R1, R3, and R4are not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: , and ; wherein R1, R2, and R4are not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: , and ; wherein R1, R2, and R3are not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from:

[0002] , and , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound having the structure: In certain embodiments, the compound having the structure selected from: , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure: . In certain embodiments, the compound having the structure selected from: , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure: ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: , and , or a pharmaceutically acceptable salt thereof. In certain embodiments, n is 0. In certain embodiments, the compound having the structure: . In certain embodiments, the compound having the structure selected from: , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: and , or a pharmaceutically acceptable salt thereof. In certain embodiments, A1is selected from –O– and –NH–; A2is selected from –C(O)– and –C(R5)(R6)–; and A3is –C(R7)(R8)–. In certain embodiments, n is 1. In certain embodiments, the compound having the structure: . In certain embodiments, the compound having the structure selected from: , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure: ( ), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound having the structure: In certain embodiments, the compound having the structure selected from: , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: ; wherein R1is not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: , and or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound having the structure: In certain embodiments, the compound having the structure selected from: , and ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having structure: ; wherein R1is not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: and , or a pharmaceutically acceptable salt thereof. In certain embodiments, R5and R6are each alkyl; or one of R5and R6is alkyl and the other of R5and R6is –H. In certain embodiments, the compound having the structure selected from: In certain embodiments, the compound having the structure selected from: wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from: and , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound having the structure: , or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound having the structure selected from: wherein one of R' and R'' is –H and the other of R' and R'' is halogen or alkyl; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having structure selected from: ; wherein R1is not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, the compound having the structure selected from:

[0003] ; or a pharmaceutically acceptable salt thereof. A further aspect of the invention relates to a compound of Formula (IB): wherein A1is–NH–; A2 is N; A3is –C(H)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof. In certain embodiments, wherein R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CH2)nC(H)(NH2)CO2H. In certain embodiments, wherein R1, R2, R3, and R4are each independently selected from –H, halogen, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CH2)nC(H)(NH2)CO2H. In certain embodiments, wherein halogen is –F. In certain embodiments, the compound having the structure selected from: wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic. In certain embodiments, wherein of R1, R2, R3, and R4are each –H. In certain embodiments, the compound having the structure: , or a pharmaceutically acceptable salt thereof. A further aspect of the invention relates to a compound having the structure: wherein R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R5and R6are both alkyl or one of R5and R6is –H and the other is alkyl ; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; q is 0 or 1; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof; provided that in Formula (IC), if q is 0; and R3is –CH2C(H)(NH2)CO2H; then at least one of R1, R2, and R4is not –H; and if q is 0; and R1is -CH2C(H)(NH2)CO2H; then at least one of R2, R3, and R4is not –H. In certain embodiments, n is 1; and R' is –H. In certain embodiments, n is 1; and R'' is –H or halogen. In certain embodiments, n is 1; and R'' is –H or alkyl. In certain embodiments, n is 1; and R'' is halogen. In certain embodiments, n is 1; and R'' is alkyl. In certain embodiments, n is 1; and R'' is –H. In certain embodiments, the absolute configuration of the chiral carbon denoted by * is (S). In certain embodiments, the absolute configuration of the chiral carbon denoted by * is (R). In certain embodiments, the boron atom in the compound is10B. In certain embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R1, the (C1-C4)alkyl or the -O-(C1- C4)alkyl can be partially or fully deuterated (e.g., -CH2CD3, -CD3, or -OCD3). Also within the scope of the invention are compounds produced comprising the natural distribution of11B and10B. Also within the scope of the invention are compounds enriched in10B, e.g., wherein the10B is present in abundance of >20%. Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent. Methods of Treatment One aspect of the invention provides compounds, compositions, and methods useful for boron neutron capture therapy. Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof a compound of Formula (I) or a pharmaceutical composition comprising a compound of Formula (I), wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons. Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof a compound of Formula (IA) or a pharmaceutical composition comprising a compound of Formula (IA), wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons. Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof a compound of Formula (IB) or a pharmaceutical composition comprising a compound of Formula (IB), wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons. Another aspect of the invention relates to a method of treating cancer, comprising: i) administering to a subject in need thereof a compound disclosed herein or a pharmaceutical composition disclosed herein, wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons. In certain embodiments, the compound selectively or preferentially accumulates in the plurality of cancer cells relative to noncancerous cells in the subject. In certain embodiments, the irradiation results in conversion of a10B atom in the compound to an -particle and a lithium-7 ion. In certain embodiments, the compound or the composition is administered intravenously. In certain embodiments, the compound is continually administered during irradiation with neutrons. In certain embodiments, in step (i) the compound is administered at about 100 mg / kg / h to about 500 mg / kg / h for a first period of time. In certain embodiments, in step (i) the compound is administered at about 150 mg / kg / h to about 300 mg / kg / h for a first period of time. In certain embodiments, the first period of time is about 1 hour to about 3 hours. In certain embodiments, the first period of time is about 2 hours. In certain embodiments, in step (ii) the compound is administered at about 50 mg / kg / h to about 150 mg / kg / h for a second period of time. In certain embodiments, in step (ii) the compound is administered at about 100 mg / kg / h to about 200 mg / kg / h for a second period of time. In certain embodiments, the second period of time is about 0.25 hour to about 1.25 hours. In certain embodiments, the second period of time is about 0.5 to about 1 hours. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is selected from head and neck cancer, glioblastoma, melanoma, sarcoma, breast cancer, meningioma, lung cancer, mesothelioma, hepatocellular carcinoma, and extramammary Paget disease. In certain embodiments, the cancer is unresectable head and neck cancer. Pharmaceutical Compositions, Routes of Administration, and Dosing In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention. Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. In certain embodiments, the pharmaceutical composition further comprises a saccharide. In certain embodiments, the pharmaceutical composition further comprises a polyhydroxy acid. In certain embodiments, the pharmaceutical composition further comprises a sugar alcohol. As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and / or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. In certain embodiments, intravenous administration of a compound may typically be from about 300 mg / kg / day to about 1000 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from about 400 mg / kg / day to about 600 mg / kg / day. In one embodiment, intravenous administration of a compound may typically be from about 450 mg / kg / day to about 500 mg / kg / day. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well- known in the art is well within the capabilities of the ordinarily skilled artisan. The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Abbreviations used in the instant specification, particularly the schemes and examples, are as follows in Table A: Example 1. Preparation of Compounds Scheme 1 Scheme 1 provides a general synthetic route to the unsubstituted oxaborole phenylalanine compounds disclosed herein. In Scheme 1, N-Boc and methyl ester of tyrosine or its isomer 1a is regioselectivity formylated under basic conditions followed by transesterification with ethanol to give 1b. Subsequent triflate formation provides 1c, which is converted to pinacol boronic ester 1d catalyzed by Pd. Sodium borohydride reduction of the aldehyde in the presence of HCl facilitates the formation of oxaborole 1e. Compound 1e is then subjected to basic hydrolysis to afford the product 1f.

[0004] Scheme 2 Scheme 2 provides a general synthetic route to the fluorinated oxaborole phenylalanine compounds disclosed herein. In Scheme 2, THP protection of bromo-fluoro-phenylene dimethanol 2a affords 2b. Subsequent cross-coupling of the bromo group of 2b under Pd catalysis provides pinacol boronic ester 2c. Under acidic condition, deprotection of the THP groups leads to cyclization with neighboring boronic acid to give oxaborole 2d. Bromination of benzylic alcohol 2d affords 2e. Coupling of 2e with either chiral diphenylmorpholinone 2f or racemic diphenylmethanimine 2g followed by deprotection affords the product 2h. Scheme 3 Scheme 3 provides a general synthetic route to the azaborole and azaborinine compounds disclosed herein. In Scheme 3, 2,6-dibromotoluene 3a is lithiated then converted to mono- pinacol boronic ester 3b. Subsequent cross-coupling of the remaining bromo group of 3b with iodide 3c under Negishi conditions provides 3d. Bromination of 3d using NBS gives benzyl bromide 3e. Nucleophilic substitution of 3e with ammonia leads to cyclization to azaborole 3f. Alternatively, nucleophilic substitution of 3e with cyano followed by reduction with Raney Ni leads to azaborinine 3g. Basic hydrolysis 3f or 3g followed by Boc deprotection affords the corresponding products 3h and 3i. Scheme 4 Scheme 4 provides a general synthetic route to the oxaborolone compounds disclosed herein. In Scheme 4, Negishi coupling of bromo-substituted ethyl 2-chlorobenzoate 4a with 3c provides 4b. The conversion of 4b to boronic acid 4c is achieved under Pd mediated cross- coupling conditions. Basic hydrolysis of ethyl ester of 4c leads to ring closure to give oxaborolone 4d. Subsequent Boc deprotection affords the product 4e.

[0005] Preparation of Compound 1

[0006] Reagents and Conditions: (a) Boc2O, NaHCO3, dioxane, H2O, rt; (b) CHCl3, NaOH, H2O, 65 °C; (c) EtOH, EDCI, DMAP, DCM, rt; (d) TEA, DMAP, DCM, rt; (e) Pd(dppf)Cl2, AcOK, dioxane, 80 °C; (f) NaBH4, MeOH, HC1, rt; (g) LiOH·H2O, MeOH, H2O, rt.

[0007] Preparation of methyl (S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (1-1)

[0008] To a stirred mixture of methyl (S)-2-amino-3-(3-hydroxyphenyl)propanoate (15 g, 76.8 mmol, 1 equiv) and NaHCO3(16 g, 192.1 mmol, 2.5 equiv) in dioxane (100 mL) and H2O (100 mL) was added di-tert-butyl dicarbonate (20 g, 92.2 mmol, 1.2 equiv) in portions. The resulting mixture was stirred for 2 h at room temperature. Then the mixture was concentrated and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to afford methyl (S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl)propanoate (20 g, 88.13%) as an off-white oil. LCMS (ESI): mass calcd. for C15H21NO5, 295.1; m / z found, 294.2 [M-H]-.

[0009] Preparation of ethyl (S)-2-[(tert-butoxycarbonyl)amino]-3-(4-formyl-3-hydroxyphenyl) propanoate (1-2)

[0010] Step A: To a stirred mixture of methyl (S)-2-[(tert-butoxycarbonyl)amino]-3-(3-hydroxyphenyl) propanoate (6 g, 20.3 mmol, 1 equiv) in CHCl3(60 mL) was added a solution of NaOH (3.25 g, 81.264 mmol, 4 equiv) in H2O (10 mL). After stirring for 3 h at 65 °C, the reaction was allowed to cool down to room temperature and quenched by the addition of water (20 mL). The resulting mixture was concentrated under reduced pressure. The aqueous layer was washed with EtOAc (3x50 mL), and then acidified to pH 3 with HCl (aq.). Then the mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (S)-2-((tert-butoxycarbonyl)amino)-3-(4-formyl-3-hydroxyphenyl)propanoic acid (5.85 g) was used in the next step directly without further purification.

[0011] Step B: To a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-formyl-3- hydroxyphenyl)propanoic acid (crude, 5.85 g), ethanol (10 mL) and DMAP (0.35 g, 2.8 mmol, 0.15 equiv) in DCM (60 mL) was added EDO (4.35 g, 22.7 mmol, 1.2 equiv) at 0 °C in portions. The resulting mixture was stirred for 3 h at room temperature. Then the mixture was diluted with DCM (40 mL) and washed with brine (3x20 mL). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to afford ethyl (2S)-2- [(tert-butoxycarbonyl)amino]-3-(4-formyl-3-hydroxyphenyl)propanoate (540 mg, 8% for two steps) as a light yellow oil. LCMS (ESI): mass calcd. for C17H23NO6, 337.2; m / z found, 336.2 [M-H]-.

[0012] Preparation of ethyl (S)-2-[(tert-butoxycarbonyl)amino]-3-[4-formyl-3- (trifluoromethanesulfonyloxy)phenyl]propanoate (1-3)

[0013] To a stirred solution of ethyl (S)-2-[(tert-butoxycarbonyl)amino]-3-(4-formyl-3-hydroxyphenyl) propanoate (740 mg, 2.2 mmol, 1 equiv), DMAP (13 mg, 0.11 mmol, 0.05 equiv) and TEA (444 mg, 4.4 mmol, 2 equiv) in DCM (10 mL) was added 1,1,1-trifluoro-N-phenyl-N- (trifluoromethanesulfonylme thyl)methanesulfonamide (977 mg, 2.6 mmol, 1.2 equiv) in portions. The resulting mixture was stirred for 3 h at room temperature. Then the reaction was quenched by the addition of water (10 mL) and diluted with DCM (10 mL). The organic layer was washed with water (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford ethyl (2S)-2-[(tert-butoxycarbonyl) amino]- 3-[4-formyl-3-(trifluoromethanesulfonyloxy)phenyl]propanoate (640 mg, 62 %) as a light yellow oil. LCMS (ESI): mass calcd. For C18H22F3NO8S, 469.1; m / z found, 468.0 [M-H]-. Preparation of ethyl (S)-2-[(tert-butoxycarbonyl)amino]-3-[4-formyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1-4)

[0014] To a stirred mixture of ethyl (S)-2-[(tert-butoxycarbonyl)amino]-3-[4-formyl-3- (trifluoromethanesulfonyloxy)phenyl]propanoate (640 mg, 1.36 mmol, 1 equiv), bis(pinacolato)diboron (588 mg, 2.3 mmol, 1.7 equiv) and AcOK (307 mg, 3.13 mmol, 2.3 equiv) in dioxane (8 mL) was added Pd(dppf)Cl2.CH2C12(122 mg, 0.15 mmol, 0.11 equiv) at room temperature. The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature and quenched by the addition of water (10 mL). The mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to afford ethyl (2S)-2-[(tert- butoxycarbonyl)amino]-3-[4-formyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]propanoate (560 mg, 91 %) as a light yellow liquid. LCMS (ESI): mass calcd. for C23H34BNO7, 447.2; m / z found, 348.3[M+H-Boc]+.

[0015] Preparation of ethyl (S)-2-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl) propanoate (1-5)

[0016] To a stirred solution of ethyl (S)-2-[(tert-butoxycarbonyl)amino]-3-[4-formyl-3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (580 mg, 1.3 mmol, 1 equiv) in MeOH (3 mL) was added NaBH4(147 mg, 3.9 mmol, 3 equiv). The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. Then to the stirred mixture was added 6 M HCl (6 mL) dropwise at room temperature. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TEA), 0% to 20% gradient in 10 min; detector, UV 220 nm. This resulted in ethyl (2S)-2-amino-3-(1-hydroxy-3H-2,1-benzoxaborol-6-yl)propanoate (160 mg, 49 %) as a light yellow oil. LCMS (ESI): mass calcd. For C12H16BNO4, 249.1; m / z found, 250.0[M+H]+.

[0017] Preparation of (S)-2-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)propanoic acid (1)

[0018] To a stirred solution of ethyl (S)-2-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6- yl)propanoate (160 mg, 0.64 mmol, 1 equiv) in MeOH (4 mL) and H2O (2 mL) was added LiOH·H2O (81 mg, 1.9 mmol, 3 equiv). The resulting mixture was stirred for 30 min at room temperature. The mixture was acidified to pH 5 with 2 N HC1 (aq.) and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: YMC- Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 20% B in 7 min, 20% B; Wave Length: 254 / 220 nm; RTl(min): 5.03) to afford (S)-2-amino-3-(l-hydroxy-l,3-dihydrobenzo[c][1,2]oxaborol-6-yl)propanoic acid (73 mg, 33.9%) as a white solid. LCMS (ESI): mass calcd. For C10H12BNO4, 221.1; m / z found, 221.95 [M+H]+.1H NMR (300 MHz, Methanol-d4) δ 7.61 (s, 1H), 7.46 - 7.39 (m, 2H), 5.09 (s, 2H), 4.25 (dd, 7 = 7.6, 5.5 Hz, 1H), 3.42 - 3.34 (m, 1H), 3.27 - 3.17 (m, 1H).

[0019] Preparation of Compounds 2-isol and 2-iso2

[0020] (R)-2-amino-3-(6-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5-yl)propanoic acid

[0021] Reagents and Conditions: (a) NBS, AIBN, CCl4, 60 °C; (b) DMSO, H2O, O2, 50 °C; (c) BH3-

[0022] THF, 50 °C; (d) DHP, TsOH, THF, DCM, r.t; (e) B2Pin2, Pd(dppf)Cl2, AcOK, 90 °C; (f) HCl

[0023] (aq ), r.t; (g) HBr (aq.), 50 °C; (h) CsCO3, TBAI, r.t.; (1) HC1 (aq.), r.t.; (j) LiOH·H2O, THF,

[0024] H2O, r.t.; (k) LiOH·H2O, THF, H2O, r.t. Preparation of 4-bromo-5-(bromomethyl)-2-fluorobenzoic acid (2-1)

[0025] To a stirred mixture of 4-bromo-2-fluoro-5 -methylbenzoic acid (3 g, 12.874 mmol, 1 equiv) in CCl4(30 mL) was added NBS (3.44 g, 19.311 mmol, 1.5 equiv) and AIBN (0.21 g, 1.287 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred overnight at 60 °C under nitrogen atmosphere. Then the mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 4-bromo-5-(bromomethyl)-2-fluorobenzoic acid (2.6 g, 64.75%) as an off- white solid. LCMS (ESI): mass calcd. for C8H5Br2FO2, 311.93; m / z found, 310.8 [M-H]+.

[0026] Preparation of 4-bromo-2-fluoro-5-(hydroxymethyl)benzoic acid (2-2)

[0027] Into a 100 mL round-bottom flask were added 4-bromo-5-(bromomethyl)-2-fluorobenzoic acid (2.6 g, 8.335 mmol, 1 equiv), DMSO (20 mL) and H2O (10 mL) at room temperature. The resulting mixture was stirred overnight at 50°C under oxygen atmosphere using an oxygen balloon. Then the mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in 4-bromo-2-fluoro-5-(hydroxymethyl)benzoic acid (1.6 g, 77.08%) as an off-white solid. LCMS (ESI): mass calcd. for C8H6BrFO3, 247.95, 249.95; m / z found, 247.1, 249.1 [M-H]+.

[0028] Preparation of (4-bromo-6-fluoro-l,3-phenylene)dimethanol (2-3)

[0029] To a stirred solution of 4-bromo-2-fluoro-5-(hydroxymethyl)benzoic acid (1.6 g, 6.425 mmol, 1 equiv) in THF (10 mL) was added BH3·THF (10 mL, 1 M in THF) dropwise at 0 °C. The resulting mixture was stirred overnight at 50 °C under nitrogen atmosphere. The reaction was quenched by the addition of MeOH. The mixture was concentrated under vacuum to afford (4- bromo-6-fluoro-l,3-phenylene)dimethanol (crude, 1.8 g) as a white solid. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C8H8BrFO2, 233.97; m / z found, 232.90 [M-H]+.

[0030] Preparation of 2,2'-(((4-bromo-6-fluoro-l,3-phenylene)bis(methylene))bis(oxy)) bis(tetrahydro-2H-pyran) (2-4)

[0031] To a stirred solution of (4-bromo-6-fluoro-l,3-phenylene)dimethanol (1.8 g, 7.658 mmol, 1 equiv) in THF (12 mL) and DCM (6 mL) were added DHP (1.93 g, 22.974 mmol, 3 equiv) and TsOH (0.13 g, 0.766 mmol, 0.1 equiv) at room temperature. The reaction mixture was stirred for 5 h at room temperature. Then the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE: EA (3: 1) to afford 2- ({4-bromo-2-fluoro-5-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (1.8 g, 58.28%) as a colorless oil. LCMS (ESI): mass calcd. for C18H24BrFO4, 402.08, 404.08; m / z found, 425, 427 [M+Na]+

[0032] Preparation of 2,2'-(((4-bromo-6-fluoro-1,3-phenylene)bis(methylene))bis(oxy)) bis(tetrahydro-2H-pyran) (2-5)

[0033] To a stirred solution of 2,2'-(((4-bromo-6-fluoro-1,3-phenylene)bis(methylene)) bis(oxy))bis(tetrahydro-2H-pyran) (1.8 g, 4.463 mmol, 1 equiv) in dioxane (20 mL) were added bis(pinacolato)diboron (2.83 g, 11.158 mmol, 2.5 equiv), AcOK (1.31 g, 13.389 mmol, 3 equiv) and Pd(dppf)Cl2(0.33 g, 0.446 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred overnight at 90 °C under nitrogen atmosphere. After completion of reaction, the mixture was filtered, the filter cake was washed with EtOAc (3x20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 2-{5-fluoro-2,4-bis[(oxan- 2-yloxy)methyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.8 g, 89.55%) as an off- white solid. LCMS (ESI): mass calcd. for C24H36BFO6, 450.26; m / z found, 473.5 [M+Na]+;

[0034] Preparation of 6-fluoro-5-(hydroxymethyl)benzo[c][l,2]oxaborol-l(3H)-ol (2-6)

[0035] A mixture of 2,2'-(((4-bromo-6-fluoro-l,3-phenylene)bis(methylene))bis(oxy))bis(tetrahydro- 2H-pyran) (1.8 g, 3.997 mmol, 1 equiv) in 6 M HCl (aq.) (20 mL) was stirred for 3 h at room temperature under nitrogen atmosphere. Then the mixture was basified to pH 6 with 3 M NaOH (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 6-fluoro-5-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (650 mg, 89.37%) as an off- white solid.1H NMR (400 MHz, DMSO-d6) δ 9.34 - 9.10 (m, 1H), 7.50 (dd, 7 = 6.0, 3.3 Hz, 1H), 7.38 (dt, 7= 9.6, 2.4 Hz, 1H), 5.33 (td, 7= 5.5, 3.2 Hz, 1H), 5.00 - 4.91 (m, 2H), 4.59 (t, 7 = 4.5 Hz, 2H).

[0036] Preparation of 5-(bromomethyl)-6-fluorobenzo[c][l,2]oxaborol-l(3H)-ol (2-7) A mixture of 6-fluoro-5-(hydroxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol (650 mg, 3.572 mmol, 1 equiv) in HBr (10 mL, 40 wt. % in water) was stirred for 6 h at 50 °C under nitrogen atmosphere. The mixture was purified directly by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-(bromomethyl)-6-fluoro-3H- 2,1-benzoxaborol-1-ol (500 mg, 57.17) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.58 (d, 7 = 6.4 Hz, 1H), 7.47 (d, 7 = 9.3 Hz, 1H), 4.98 (s, 2H), 4.73 (s, 2H).

[0037] Preparation of methyl 2-((diphenylmethylene)amino)-3-(6-fluoro-1-hydroxy-l,3- dihydrobenzo[c] [1,2]oxaborol-5-yl)propanoate (2-8)

[0038] To a stirred solution of 5-(bromomethyl)-6-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (500 mg, 2.042 mmol, 1 equiv) in anhydrous MeCN (10 mL) were added methyl 2- [(diphenylmethylidene) amino]acetate (775.89 mg, 3.063 mmol, 1.5 equiv), TBAI (75.43 mg, 0.204 mmol, 0.1 equiv) and CS2CO3(1330.69 mg, 4.084 mmol, 2 equiv). The resulting mixture was stirred for 5 h at room temperature. The mixture was concentrated under vacuum and the crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C24H21BFNO4, 417.15; m / z found, 418.4 [M+H]+;

[0039] Preparation of methyl (S)-2-amino-3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo [c][1,2]oxaborol-5-yl)propanoate(2-9a) and methyl (R)-2-amino-3-(6-fluoro-1-hydroxy-1,3- dihydrobenzo[c]

[0112] oxaborol-5-yl)propanoate (2-9b)

[0040] A mixture of methyl 2-[(diphenylmethylidene)amino]-3-(6-fluoro-1-hydroxy-3H-2,1- benzoxaborol-5-yl)propanoate(crude) in 6 M HCl (aq.) (10 mL) was stirred for 5 h at room temperature under nitrogen atmosphere. Then the mixture was basified to pH 8 with 2 M NaOH(aq.), and purified by Prep-HPLC with the following conditions (Column: XBridge Prep Amide OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN (0.1% FA); Flow rate: 50 mL / min; Gradient: 95% B to 79% B in 10 min, 79% B; Wave Length: 220 nm; RTl(min): 6.50 / 8.50;) to afford methyl 2-amino-3-(6-fluoro-1-hydroxy-3H-2,1- benzoxaborol-5-yl)propanoate (160 mg, 37.67%) as a light yellow solid. This racemic product (160 mg) was separated by Prep-Chiral- HPLC with the following conditions (Column: CHIRALCEL AY-H, 2*25 cm, 5 pm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 19.5 min; Wave Length: 224 / 274 nm; RTl(min): 5.8; RT2(min): 13.075; Sample Solvent: EtOH— HPLC; Injection Volume: 0.8 mL; Number Of Runs: 6) to afford methyl (S)-2-amino-3-(6-fluoro-1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-5-yl)propanoate (40 mg, 25.0%, ee>99%, 1stisomer on HPLC) as an off-white solid and methyl (R)-2-amino-3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo [c][1,2]oxaborol-5-yl)propanoate (45 mg, 28.12%, ee>99%, 2ndisomer on HPLC) as an off- white solid. LCMS (ESI): mass calcd. for C11H13BFNO4, 253.09; m / z found, 254.0 [M+H]+;

[0041] Preparation of (S)-2-amino-3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5- yl)propanoic acid (2-isol)

[0042] A mixture of methyl (S)-2-amino-3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5- yl)propanoate (40 mg, 0.158 mmol, 1 equiv) and LiOH·H2O (19.9 mg, 0.474 mmol, 3 equiv) in THE (1.5 mL) and H2O (0.5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. Then the mixture was acidified to pH 5 with HC1 (aq.) and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Amide OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN (0.1% FA); Flow rate: 50 mL / min; Gradient: 95% B to 79% B in 10 min, 79% B; Wave Length: 220 nm; RTl(min): 6.50 / 8.50;) to afford (S)-2-amino-3- (6-fluoro-1-hydroxy-l,3-dihydrobenzo[c][1,2]oxaborol-5-yl)propanoic acid (7 mg, 18.01%) as a white solid. LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240.15 [M+H]+;1H NMR (400 MHz, Methanol-d4) δ 7.35 (dd, 7= 29.7, 7.9 Hz, 2H), 4.99 (s, 2H), 3.98 (dd, 7 = 8.0, 5.3 Hz, 1H), 3.39 (dd, 7= 14.6, 5.4 Hz, 1H), 3.15 (dd, 7 = 14.5, 8.0 Hz, 1H).

[0043] Preparation of (R)-2-amino-3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5- yl)propanoic acid (2-iso2)

[0044] A mixture of methyl (R)-2-amino-3-(6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5- yl)propanoate(45 mg, 0.178 mmol, 1 equiv) and LiOH·H2O (22.4 mg, 0.534 mmol, 3 equiv) in THE (1.5 mL) and H2O (0.5 mL) was stirred for 2 h at room temperature under nitrogen atmosphere. Then the mixture was acidified to pH 5 with HC1 (aq.) and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Amide OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN(0.1% FA); Flow rate: 50 mL / min; Gradient: 95% B to 79% B in 10 min, 79% B; Wave Length: 220 nm; RTl(min): 6.50 / 8.50;) to afford (R)-2-amino-3- (6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)propanoic acid (13 mg, 30.06%) as a white solid. LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240.10 [M+H]+;1H NMR (400 MHz, Methanol-d4) 7.35 (t, J = 7.1 Hz, 2H), 5.00 (s, 2H), 3.85 (s, 1H), 3.53 – 3.40 (m, 1H), 3.09 (dd, J = 14.8, 8.6 Hz, 1H). Preparation of Compound 3 aReagents and Conditions: (a) NBS, Na2S2O8, Pd(OAc)2, TfOH, DCE, 90oC; (b) NBS, AIBN, ACN, 80oC; (c) DMSO, H2O, O2, 50oC; (d) LiBH4(2M in THF), THF, MeOH, rt; (e) DHP, HCl, rt; (f) B2Pin2, Pd(dppf)Cl2, AcOK, dioxane, 90oC; (g) HCl(aq.), MeOH, rt; (h) HBr(48% in water), rt; (i) NaHMDS, HMPA, THF, -78oC; (j) TFA, DCM, rt; (k) Pd / C, Pd(OH)2 / C, THF, rt. Preparation of ethyl 2-bromo-3-fluoro-6-methylbenzoate (3-1) To a stirred mixture of ethyl 5-fluoro-2-methylbenzoate (10 g, 54.89 mmol, 1 equiv) and NBS (10.75 g, 60.38 mmol, 1.1 equiv) in DCE (150 mL) were added sodium persulfate (26.14 g, 109.78 mmol, 2.0 equiv), Pd(OAc)2(616.1 mg, 2.74 mmol, 0.05 equiv) and trifluoromethanesulfonic acid (20.59 g, 137.22 mmol, 2.5 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 90 °C overnight. The mixture was quenched with saturated NaHCO3(aq.). The resulting mixture was extracted with CH2Cl2(3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to give the title product as a light yellow oil (9.32 g, 65.0%). LCMS (ESI): mass calcd. for C10H10BrFO2, 256.0 302.1 [M+H+CH3CN]+. Preparation of ethyl 2-bromo-6-(bromomethyl)-3-fluorobenzoate (3-2) To a stirred solution of ethyl 2-bromo-3-fluoro-6-methylbenzoate (9.32 g, 35.70 mmol, 1 equiv) in CH3CN (180 mL) were added NBS (7.62 g, 42.84 mmol, 1.2 equiv) and AIBN (586.2 mg, 3.57 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to give the title product as a yellow oil (10.1 g, 83.2%). LCMS (ESI): mass calcd. for C10H9Br2FO2, 337.9 No MS signal on LCMS. Preparation of 7-bromo-6-fluoroisobenzofuran-1(3H)-one (3-3) A mixture of ethyl 2-bromo-6-(bromomethyl)-3-fluorobenzoate (10.1 g, 29.71 mmol, 1 equiv) in DMSO (40 mL) / H2O (20 mL) was stirred at 50 °C overnight under oxygen atmosphere by using O2balloon. Then the mixture was diluted with H2O (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to give the title product as an off-white solid (4.2 g, 61.2%). LCMS (ESI): mass calcd. for C8H4BrFO2, 230.0 ; m / z found, 231.0 [ M+H]+. Preparation of (3-bromo-4-fluoro-1,2-phenylene)dimethanol (3-4) To a stirred solution of 7-bromo-6-fluoroisobenzofuran-1(3H)-one (4.2 g, 18.18 mmol, 1 equiv) in THF (60 mL) under nitrogen atmosphere at 0 °C were added LiBH4(2M in THF) (9.09 mL, 18.18 mmol, 1 equiv) and MeOH (1.2 mL) dropwise. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with MeOH. The mixture was concentrated, diluted with water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title product as a white solid (4.15 g, crude). LCMS (ESI): mass calcd. for C8H8BrFO2, 234.0; m / z found, 233.0 [M-H]" Preparation of 2,2'-(((3-bromo-4-fluoro-1,2-phenylene)bis(methylene))bis(oxy))bis (tetrahydro-2H-pyran) (3-5)

[0045] To a stirred solution of (3-bromo-4-fluoro-1,2-phenylene)dimethanol (4.15 g, 17.65 mmol, 1 equiv) in DHP (80 mL) was added cone. HCl (0.3 mL, 12 mol / L) dropwise. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to give the title product as a colorless oil (7.0 g, 98.3%).LCMS (ESI): mass calcd. for C18H24BrFO4, 402.1; m / z found, 425.2 [M+Na]+.

[0046] Preparation of 2-(6-fluoro-2,3-bis(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)-4, 4,5,5- tetramethyl-1,3,2-dioxaborolane (3-6)

[0047] To a stirred solution of 2,2'-(((3-bromo-4-fluoro-1,2-phenylene)bis(methylene))bis(oxy)) bis(tetrahydro-2H-pyran) (7 g, 17.36 mmol, 1 equiv) in dioxane (140 mL) were added bis(pinacolato)diboron (11.02 g, 43.40 mmol, 2.5 equiv) , AcOK (5.11 g, 52.07 mmol, 3 equiv) and Pd(dppf)Cl2(1.27 g, 1.74 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at 90 °C overnight. Then the mixture was filtered, the solid was washed with EtOAc (2x10 mL). The filtrate was concentrated, diluted with water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title product as a brown oil (7.8 g, crude). LCMS (ESI): mass calcd. for C24H36BFO6, 450.3; m / z found, 473.4 [M+Na]+.

[0048] Preparation of 7-fluoro-4-(hydroxymethyl)benzo[c][1,2]oxaborol-l(3H)-ol (3-7)

[0049] To a stirred solution of 2-(6-fluoro-2,3-bis(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.8 g, crude) in MeOH (65 mL) was added 6 M HCl (aq., 13 mL). The resulting mixture was stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 5% to 30% gradient in 10 min; detector, UV 220 nm] to give the title product as a white solid (3.0 g, 95.2%). LCMS (ESI): mass calcd. for C8H8BFO3, 182.1; no MS signal on LCMS.

[0050] Preparation of 4-(bromomethyl)-7-fluorobenzo[c][1,2]oxaborol-l(3H)-ol (3-8)

[0051] A mixture of 7-fluoro-4-(hydroxymethyl)benzo[c][1,2]oxaborol-1(3H)-ol (3 g, 16.49 mmol, 1 equiv) in HBr in water(48%) (50 mL) was stirred at room temperature for 2 days. Then the mixture was diluted with water (100 mL), and extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (1x60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3: 1) to give the title product as a light yellow solid (1.39 g, 34.4%). LCMS (ESI): mass calcd. for C8H7BBrFO2, 244.0; m / z found, 260.9 [M+ H2O-H]-. Preparation of tert-butyl (3S,5S,6R)-3-((7-fluoro-1-hydroxy-1,3-dihydrobenzo [c][1,2]oxaborol-4-yl)methyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate (3-9)

[0052] To a stirred solution of 4-(bromomethyl)-7-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (1.7 g, 6.94 mmol, 1 equiv) and tert-butyl (2R,3S)-6-oxo-2,3-diphenylmorpholine-4-carboxylate (2.45 g, 6.94 mmol, 1 equiv) in THE (34 mL) ZHMPA (3.4 mL) under nitrogen atmosphere at -78 °C was added NaHMDS (5.21 mL, 2 mol / L, 1.5 equiv) dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 2 h and at room temperature for 2 h. The reaction was quenched with sat. NH4CI (aq.). The mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (2.29 g, 63.8%). LCMS (ESI): mass calcd. for C29H29BFNO6, 517.2; m / z found, 418.3 [M-Boc+H]+.

[0053] Preparation of (3S,5S,6R)-3-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)methyl)-5,6-diphenylmorpholin-2-one (3-10)

[0054] To a stirred mixture of tert-butyl (3S,5S,6R)-3-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2] oxaborol-4-yl)methyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate (1 g, 1.93 mmol, 1 equiv) in DCM (10 mL) was added TEA (2 mL). The resulting mixture was stirred at room temperature for 2 h. Then the mixture was concentrated under reduced pressure to give the title product as a light yellow solid (800 mg, crude). LCMS (ESI): mass calcd. for C24H21BFNO4, 417.2; m / z found, 418.3 [M+H]+.

[0055] Preparation of (S)-2-amino-3-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)propanoic acid (3)

[0056] To a stirred solution of (3S,5S,6R)-3-((7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)methyl)-5,6-diphenylmorpholin-2-one (800 mg, crude) in THF (16 mL) were added Pd / C (160 mg, 10%) and Pd(OH)2 / C (160 mg, 10%) at room temperature. The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere by using H2balloon. Then the mixture was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by Prep-HPLC [with the following conditions (Column: Atlantis Prep T3 OBD Column, 19* 150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: isocratic 0% B to 10% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.57)] to afford the title product as a white solid (152.5 mg, 33.3%). LCMS (ESI): mass calcd. for C10H11BFNO4, 239.1; m / z found, 240.1 [M+H]+.1H NMR (400 MHz, Deuterium Oxide) δ 6.94 (dd, J = 8.2, 5.1 Hz, 1H), 6.72 (t, J= 7.9 Hz, 1H), 4.69 (s, 2H), 3.34 (dd, J = 7.9, 5.9 Hz, 1H), 2.76 (dd, 7 = 13.8, 6.0 Hz, 1H), 2.54 (dd, 7 = 13.8, 8.0 Hz, 1H).

[0057] Preparation of Compound 4 Reagents and Conditions: (a) NaBH4, MeOH, r.t.; (b) BnBr, K2CO3, DMF, r.t.; (c) B2(OH)4, Xphos-Pd G2, Xphos, AcOK, EtOH, 80°C; (d) NBS, DMF, r.t.; (e) NHC, pyridine, Ir(ppy)2(dtbbpy)PF6, NiBr.dtbbpy, quinuclidine, MTBE, DMA, blue LEDs, r.t.; (f) LiOH, THF, H2O, r.t.; (g) 4M HCl, 1,4-dioxane, r.t.; (h) Pd(OH)2 / C, MeOH, H2O, r.t.;

[0058] Preparation of 2-bromo-3-(hydroxymethyl)phenol (4-1)

[0059] A solution of 2-bromo-3-hydroxybenzaldehyde (4.3 g, 21.4 mmol, 1 equiv) and NaBH4(2.43 g, 64 mmol, 3 equiv) in MeOH (80 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction was quenched with water(100 mL) at 0 °C. The mixture was acidified to ‘pH 4’ with 2 M HCl (aq.). The resulting mixture was extracted with DCM (4 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title product as an off-white solid (4.2 g, 96.70%). LCMS (ESI): mass calcd. for C7H7BrO2, 201.96; m / z found, 200.90 [M-H]-.

[0060] Preparation of [3-(benzyloxy)-2-bromophenyl]methanol (4-2)

[0061] To a stirred mixture of 2-bromo-3-(hydroxymethyl)phenol (10.2 g, 50.2 mmol, 1 equiv) and K2CO3(13.89 g, 100 mmol, 2 equiv) in DMF (150 mL) was added BnBr (10.31 g, 60.3 mmol,

[0062] 1.2 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. The mixture was poured into the ice water. The precipitated solids were collected by filtration and washed with water (3 x 10 mL) to afford the title product as a white solid (14.2 g, crude).1H NMR (400 MHz, Chloroform-d) 57.52 - 7.45 (m, 2H), 7.39 (t, 7= 7.5 Hz, 2H), 7.36 - 7.29 (m, 1H), 7.27 - 7.23 (m, 1H), 7.11 (d, 7= 7.6 Hz, 1H), 6.90 (d, 7 =

[0063] 8.2 Hz, 1H), 5.17 (s, 2H), 4.78 (s, 2H).

[0064] Preparation of 7-(benzyloxy)benzo[c][1,2]oxaborol-l(3H)-ol (4-3)

[0065] To a stirred solution of [3 -(benzyloxy)-2-bromophenyl] methanol (7.2 g, 24.6 mmol, 1 equiv) and tetrahydroxydiborane (6.61 g, 73.7 mmol, 3 equiv) in EtOH (100 mL) were added X-Phos Pd G2 (3.86 g, 4.9 mmol, 0.2 equiv), X-Phos (1.17 g, 2.46 mmol, 0.1 equiv) and KOAc (7.23 g, 73.7 mmol, 3 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 3 h. The resulting mixture was filtered, and the solid was washed with EtOAc (3 x 20 mL). The combined filtrate was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 30% to 50% gradient in 6 min; detector, UV 220 nm] to afford the title product as a light yellow solid(3.4 g, 57.67%). LCMS (ESI): mass calcd. for C14H213BO3, 240.10; m / z found, 239.15 [M -H]- .

[0066] 1.eparation of 7-(benzyloxy)-4-bromobenzo[c][1,2]oxaborol-1(3H)-ol (4-4)

[0067] To a stirred solution of 7-(benzyloxy)benzo[c][1,2]oxaborol-1(3H)-ol (3.4 g, 14.2 mmol, 1 equiv) in DMF (40 mL) was added NBS (2.27 g, 12.7 mmol, 0.9 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 4 h. The resulting solution was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 65% gradient in 10 min; detector, UV 220 nm] to afford the title product as an off-white solid (1.5 g, 33.21%). LCMS (ESI): mass calcd. for C14H12BBrO3, 318.01; m / z found, 317.00 [M -H]- Preparation of methyl (S)-3-(7-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)-2-((tert-butoxycarbonyl)amino)propanoate (4-5) An oven-dried 40 mL vial was charged with methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoate (191 mg, 0.87 mmol, 1.75 equiv) and 5,7-di-tert-butyl-3-phenyl-1,3$1^{5}-benzoxazol-3-ylium (315 mg, 0.80 mmol, 1.6 equiv). After the vial was vacuumed and refilled with nitrogen gas twice. MTBE (4 mL) was added and the reaction at r.t. for 10 min. Then, Pyridine (63 mg, 0.80 mmol, 1.6 equiv) in MTBE (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 10 min. Another oven-dried 40 mL vial was charged with Ir(ppy)2(dtbbpy)PF6(6.8 mg, 0.007 mmol, 0.015 equiv), NiBr.dtbbpy (12 mg, 0.025 mmol, 0.05 equiv), quinuclidine (97 mg, 0.87 mmol, 1.75 equiv), 2, 3-dihydro-1H-isoindole- 1,3-dione (18 mg, 0.12 mmol, 0.25 equiv) and 7-(benzyloxy)-4- bromobenzo[c][1,2]oxaborol- 221H)-ol (159 mg, 0.50 mmol, 1 equiv). DMA (5 mL) was added to this vial under an atmosphere of nitrogen. The MTBE suspension to a 10 mL syringe under air. Then a syringe filter and new needle were installed on the syringe, before the MTBE solution was injected through the syringe filter into the DMA solution. The vial was stirred at 1500 rpm stir rate and irradiated under 450 nm LED modules at 100% light intensity with maxed fan speed of 1500 rpm stirring rate overnight. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water ( 10mmol / L NH4HCO3), 30% to 60% gradient in 10 min; detector, UV 220 nm] to afford the title product as an off-white solid (270 mg, 61.37%). The reaction was repeated one more batch (SM: 318 mg), and 270 mg of product was obtained in total. LCMS (ESI): mass calcd. for C23H28BNO7, 441.20; m / z found, 464.15 [M+Na]+.

[0068] Preparation of (S)-3-(7-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4-yl)-2- ((tert-butoxycarbonyl)amino)propanoic acid (4-6)

[0069] To a stirred mixture of methyl (S)-3-(7-(benzyloxy)-1-hydroxy-1,3- dihydrobenzo[c][1,2]oxaborol-4-yl)-2-((tert-butoxycarbonyl)amino)propanoate (270 mg, 0.61 mmol, 1 equiv) in THE (4 mL) / H2O (2 mL) was added LiOH.H2O (51 mg, 1.22 mmol, 2 equiv) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The mixture was acidified to ‘pH 6’ with formic acid. The resulting solution was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 40% to 55% gradient in 5 min; detector, UV 220 nm] to afford the title product as a white solid(243 mg, 92.96%). LCMS (ESI): mass calcd. for C22H26BNO7, 427.18; m / z found,369.15 [M-t-Bu+H]+.

[0070] Preparation of (S)-2-amino-3-(7-(benzyloxy)-1-hydroxy-l,3-dihydrobenzo[c][1,2]oxaborol- 4-yl)propanoic acid (4-7)

[0071] To a stirred solution of (S)-3-(7-(benzyloxy)-1-hydroxy- 1 ,3-dihydrobenzo[c][1 ,2]oxaborol-4-yl)- 2-((tert-butoxycarbonyl)amino)propanoic acid (233 mg, 0.54 mmol, 1 equiv) in dioxane (2.5 mb) was added 4 M HCl in 1,4-dioxane (2.5 mb) under nitrogen atmosphere at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 1 h. The resulting mixture was diluted with water (2 mb). The resulting solution was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 30% gradient in 4 min; detector, UV 220 nm] to afford the title product as a white solid (160 mg, 89.69%). LCMS (ESI): mass calcd. for C17H18BNO5, 327.13; m / z found, 369.20 [M+H+MeCN]+.

[0072] Preparation of (S)-2-amino-3-(1,7-dihydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)propanoic acid (4)

[0073] A mixture of (S)-2-amino-3-(7-(benzyloxy)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)propanoic acid (50 mg, 0.15 mmol, 1 equiv) and Pd(OH)2 / C (20 mg) in MeOH (5 mb) and H2O (0.5 mL) was stirred under 5 atm hydrogen atmosphere at room temperature for 2 h. The resulting mixture was filtered, the filtrate was purified by Prep-HPLC [with the following conditions Column: XBridge Prep Amide OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 95%B to 84%B in 10 min; Wave Length: 200 / 220 nm; RTl(min): 6.63; Number Of Runs: 3] to afford the title product as a white solid(6 mg, 11.18%). LCMS (ESI): mass calcd. for C10H12BNO5, 237.08; m / z found, 237.90 [M+H]+.1H NMR (400 MHz, Deuterium Oxide): 57.22 (d, 7 = 8.2 Hz, 1H), 6.75 (d, 7 = 8.1 Hz, 1H), 5.00 (s, 2H), 4.06 - 3.90 (m, 1H), 3.18 - 3.04 (m, 1H), 2.99 - 2.87 (m, 1H).

[0074] Preparation of Compound 5

[0075] Reagents and Conditions: (a) NBS, AIBN, ACN, 80 °C; (b) DMSO, H2O, O2, 50 °C; (c) LiBH4, THF, rt; (d) DHP, HCl, rt; (e) B2Pin2, Pd(dppf)Cl2, AcOK, dioxane, 90 °C; (f) HCl, MeOH, rt; (g) HBr, rt; (h) NaHMDS, HMPA, THF, -78 °C; (i) TFA, DCM, rt; (j) Pd / C, Pd(OH)2 / C, THF, rt.

[0076] Preparation of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (5-1) A mixture of methyl 3-bromo-5-fluoro-2-methylbenzoate (5 g, 20.24 mmol, 1 equiv), NBS (4.32 g, 24.29 mmol, 1.2 equiv) and AIBN (0.33 g, 2.024 mmol, 0.1 equiv) in MeCN (50 mL) was stirred under nitrogen atmosphere at 80 °C for overnight. Then the mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C9H7Br2FO2, 325.88; m / z found, 325 [M +H]+.1H NMR (400 MHz, Chloroform-d) 57.60 (dd, J = 8.8, 2.8 Hz, 1H), 7.50 (dd, J = 7.4, 2.8 Hz, 1H), 5.07 (s, 2H), 3.95 (s, 3H).

[0077] Preparation of methyl 4-bromo-6-fluoro-3H-2-benzofuran-1-one (5-2)

[0078] A mixture of methyl 3-bromo-2-(bromomethyl)-5-fluorobenzoate (6 g, 18.41 mmol, 1 equiv) in DMSO (40 mL) and H2O (20 mL) was stirred at 55 °C for overnight under O2atmosphere by using oxygen balloon. Then the mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 60% gradient in 10 min; detector, UV 220 nm] to afford the title product as a white solid (3.5 g, 82.3%). LCMS (ESI): mass calcd. for C8H4BrFO4, 229.94; m / z found, 229 [M-H]+.

[0079] Preparation of [2-bromo-4-fluoro-6-(hydroxymethyl)phenyl]methanol (5-3)

[0080] To a stirred solution of 4-bromo-6-fluoro-3H-2-benzofuran-1-one (3.5 g, 15.150 mmol, 1 equiv) in THE (45 mL) under nitrogen atmosphere at 0 °C was added LiBH4(7.6 mL, 15.20 mmol, 2 mol / L in THE) dropwise. The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. The reaction was quenched with MeOH. The mixture was concentrated, diluted with water (100 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 15 min; detector, UV 220 nm] to afford the title product (3 g, 84.24%) as a white solid. LCMS (ESI): mass calcd. for C8H8Br2FO2, 233.97; m / z found, 233 [M-H]+.

[0081] Preparation of 2-({3-bromo-5-fluoro-2-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (5-4)

[0082] A mixture of [2-bromo-4-fluoro-6-(hydroxymethyl)phenyl]methanol (3 g, 12.76 mmol, 1 equiv) and cone. HCl (0.2 mL) in DHP (60 mL) was stirred at room temperature for overnight. The raction was quenched with saturated NaHCO3(aq.). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 50% to 100% gradient in 10 min; detector, UV 254 / 220 nm] to afford the title product as a brown yellow oil (4.1 g, 79.7%).

[0083] LCMS (ESI): mass calcd. for C18H24BrFO4, 402.08; m / z found, 425 [M+Na]+

[0084] Preparation of 2-{5-fluoro-2,3-bis[(oxan-2-yloxy)methyl]phenyl}-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (5-5)

[0085] To a stirred solution of 2-({3-bromo-5-fluoro-2-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (4.1 g, 10.17 mmol, 1 equiv) in dioxane (80 mL) were added bis(pinacolato)diboron (6.45 g, 25.42 mmol, 2.5 equiv), Pd(dppf)Cl2(0.74 g, 1.02 mmol, 0.1 equiv) and AcOK (2.99 g, 30.50 mmol, 3 equiv) in portions. The resulting mixture was stirred under nitrogen atmosphere at 90 °C for overnight. The reaction was quenched by the addition of water (40 mL). The mixture was concentrated, and extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine (1x 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was used directly in the next step without further purification (4.0 g, crude). LCMS (ESI): mass calcd. for C24H36BFO6, 450.26; m / z found, 473 [M+Na]+

[0086] Preparation of 6-fluoro-4-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (5-6)

[0087] To a stirred solution of 2-{5-fluoro-2,3-bis[(oxan-2-yloxy)methyl]phenyl}-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (4.0 g, crude) in MeOH (40 mL) were added 6 M HCl (aq. 10 mL) slowly. The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 15 min; detector, UV 220 nm] to provide the title product (1.6 g, 99.0%) as a white solid. LCMS (ESI): mass calcd. for C8H8BFO3, 182.06; m / z found, 181 [M-H]+

[0088] Preparation of 4-(bromomethyl)-6-fluoro-3H-2,1-benzoxaborol-1-ol (5-7)

[0089] A solution of 6-fluoro-4-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (1.5 g, 8.24 mmol, 1 equiv) in HBr (48% in water, 30 mL) was stirred at room temperature for overnight. Then the mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow solid (1.4 g, 69.4%). LCMS (ESI): mass calcd. for C8H7BBrFO2;244.85 m / z found, 243 [M-H]+

[0090] Preparation of tert-butyl (3S,5S,6R)-3-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborol-4- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (5-8)

[0091] To a stirred mixture of 4-(bromomethyl)-6-fluoro-3H-2,1-benzoxaborol-1-ol (1.3 g, 5.31 mmol, 1 equiv) and tert-butyl (2R,3S)-6-oxo-2,3-diphenylmorpholine-4-carboxylate (1.88 g, 5.31 mmol, 1 equiv) in THE (30 mL) and HMPA (3.0 mL) under nitrogen atmosphere at -78 °C was added 2 mol / L NaHMDS (6.7 mL, 13.27 mmol, 2.5 equiv) dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 2 h and at room temperature for 2 h. The reaction was quenched with sat. NH4CI (aq.). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow solid (750 mg, 27.3%). LCMS (ESI): mass calcd. for C29H29BFNO6; 517.36 m / z found,418 [M-Boc+H]+

[0092] Preparation of (3S,5S,6R)-3-((6-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)methyl)-5,6-diphenylmorpholin-2-one (5-9)

[0093] To a stirred solution of tert-butyl (3S,5S,6R)-3-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborol-4- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (750 mg, 1.45 mmol, 1 equiv) in DCM (6 mL) was added TEA (2 mL) slowly. The resulting mixture was stirred at room temperature for 3 h. Then the mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C24H21BFNO4;417.24 m / z found, 418 [M+H]+

[0094] Preparation of (2S)-2-amino-3-(6-fluoro-1-hydroxy-3H-2,1-benzoxaborol-4-yl)propanoic acid (5)

[0095] To a stirred solution of (3S,5S,6R)-3-[(6-fluoro-1-hydroxy-3H-2,1-benzoxaborol-4-yl)methyl]- 5,6-diphenylmorpholin-2-one (400 mg, 0.959 mmol, 1 equiv) in THE (10 mL) were added Pd / C (80 mg, 10%) and Pd(OH)2 / C (80 mg, 10%) in portions. The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere by using H2balloon. Then the mixture was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by reverse flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 100% gradient in 15 min; detector, UV 220 nm] to provide the title product as a white solid (45 mg, 18.9%). LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240 [M+H],1H NMR (400 MHz, Deuterium Oxide) 56.92 (dd, J = 8.5, 2.4 Hz, 1H), 6.71 (dd, 7 = 10.6, 2.5 Hz, 1H), 4.66 (s, 2H), 3.37 (dd, 7 = 8.0, 5.9 Hz, 1H), 2.79 (dd, 7= 13.7, 5.9 Hz, 1H), 2.55 (dd, 7= 13.8, 8.1 Hz, 1H).

[0096] Preparation of Compound 6

[0097] Reagents and Conditions: (a) NBS, AIBN, CH3CN, 80 °C; (b) DMSO, H2O, O2, 50 °C; (c) BH3- THF, THF; (d) DHP, HCl, rt. (e) (1) B2Pin2, Pd(dppf)Cl2, AcOK, dioxane, 80 °C; (2) HCl, MeOH, rt; (f) HBr, rt; (g) NaHMDS, HMPA, THF; (h) TFA, DCM, rt; (i) Pd / C, Pd(OH)2 / C, THF, rt.

[0098] Preparation of methyl 6-bromo-3-(bromomethyl)-2-fluorobenzoic acid (6-1)

[0099] To a stirred 6-bromo-2-fluoro-3-methylbenzoic acid (5 g, 21.46 mmol, 1 equiv) and AIBN (0.18 g, 1.07 mmol, 0.05 equiv) in ACN (50 mL) was added NBS (3.82 g, 21.46 mmol, 1 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C overnight. Then the mixture was concentrated, diluted with water (40 mL), and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 60% gradient in 20 min; detector, UV 220 nm] to provide the title product as a light yellow solid (5.8 g, 86.7%). LCMS (ESI): mass calcd. for C8H5Br2FO2, 309.86; m / z found, 311 [M+H]+.

[0100] Preparation of methyl 6-bromo-2-fluoro-3-(hydroxymethyl)benzoic acid (6-2)

[0101] A mixture of methyl 6-bromo-3-(bromomethyl)-2-fluorobenzoic acid (5.4 g, 17.31 mmol, 1 equiv) in DMSO / H2O (20 mL / 10 mL) was stirred at 50 °C for overnight under O2atmosphere by using oxygen balloon. Then the mixture was diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 30% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (3.4 g, 78.9%). LCMS (ESI): mass calcd. for C8H6BrFO3, 247.95; m / z found, 249 [M+H]+.

[0102] Preparation of [4-bromo-2-fluoro-3-(hydroxymethyl)phenyl]methanol (6-3)

[0103] To a stirred mixture of 6-bromo-2-fluoro-3-(hydroxymethyl)benzoic acid (3.4 g, 13.65 mmol, 1 equiv) in THE (60 mL) under nitrogen atmosphere at 0 °C was added BH3-THF (41 mL, 40.96 mmol, 3 equiv, 1 mol / L in THE) dropwise. The resulting mixture was stirred under nitrogen atmosphere at 50 °C overnight. The reaction was quenched by the addition of MeOH slowly at 0 °C. The mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C8H8BrFO2, 233.97; m / z found, 235 [M+H]+.

[0104] Preparation of 2-({6-bromo-2-fluoro-3-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (6-4)

[0105] To a stirred mixture of [4-bromo-2-fluoro-3-(hydroxymethyl)phenyl]methanol (3.5 g, crude) in DHP (50 mL) was added cone. HCl (0.07 mL, 12 mol / L). The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to provide the title product as a colorless oil (5.4 g, 89.9%). LCMS (ESI): mass calcd. for C18H24BrFNO4, 402.08; m / z found, 403 [M+H]+.

[0106] Preparation of 4-fluoro-5-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (6-5)

[0107] Step 1: To a stirred mixture of 2-({6-bromo-2-fluoro-3-[(oxan-2-yloxy)methyl]phenyl} methoxy) oxane (5.4 g, 13.39 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3,2-dioxaborolane (10.20 g, 40.17 mmol, 3 equiv) and AcOK (3.94 g, 40.17 mmol, 3 equiv) in dioxane (54 mL) was added Pd(dppf)Cl2.CH2Cl2(1.09 g, L34 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C overnight. Then the mixture was filtered. The filtrate was concentrated, diluted with water (80 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0108] Step 2: To a stirred mixture of 2-{3-fluoro-2,4-bis[(oxan-2-yloxy)methyl]phenyl}-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (5.4 g, crude) in MeOH (60 mL) was added HCl (6 M) (15 mL, aq.) slowly. The resulting mixture was stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 220 nm] to give the title product as a light yellow solid (1.24 g, 51%). LCMS (ESI): mass calcd. for C8H8BFO3, 182.06; m / z found, 183 [M+H]+.

[0109] Preparation of 5-(bromomethyl)-4-fluoro-3H-2,1-benzoxaborol-1-ol (6-6)

[0110] A solution of 4-fluoro-5-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (4 g, 21.98 mmol, 1 equiv) in HBr (40 mL, 48% in water) was stirred at room temperature overnight. Then the mixture was diluted with water (40 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 40% to 50% gradient in 15 min; detector, UV 220 nm] to give the title product as a light yellow solid (2.2 g, 40.8%). LCMS (ESI): mass calcd. for C8H7BBrFO2, 243.97; m / z found, 245 [M+H]+. Preparation of tert-butyl (3S,5S,6R)-3-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (6-7)

[0111] To a stirred mixture of 5-(bromomethyl)-4-fluoro-3H-2,1-benzoxaborol-1-ol (2.4 g, 9.80 mmol, 1 equiv) and tert-butyl (2R,3S)-6-oxo-2,3-diphenylmorpholine-4-carboxylate (3.45 g, 9.80 mmol, 1 equiv) in HMPA (4.8 mL) and THF (48 mL) under nitrogen atmosphere at -78 °C was added NaHMDS (7.35 mL, 2 mol / L in THF, 1.5 equiv) dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 1 h, and at room temperature for 2 h. The reaction was quenched with sat. NH4CI (aq.). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 80% to 90% gradient in 15 min; detector, UV 220 nm] to afford the title product as a light yellow solid (2.4 g, 47.3%). LCMS (ESI): mass calcd. for C29H29BFNO6, 517.21; m / z found, 418 [M+H-Boc]+. Preparation of (3S,5S,6R)-3-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyl]-5,6- diphenylmorpholin-2-one (6-8)

[0112] To a stirred mixture of tert-butyl (3S,5S,6R)-3-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (1.2 g, 1 equiv) in DCM (9 mL) was added TEA (3 mL) slowly. The resulting mixture was stirred at room temperature for 2 h, and then concentrated. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C24H21BFNO4, 417.15; m / z found, 418 [M+H]+.

[0113] Preparation of (2S)-2-amino-3-(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)propanoic acid (6)

[0114] A mixture of (3S,5S,6R)-3-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-5-yl)methyl]-5,6- diphenylmorpholin-2-one (1 g, crude), Pd(0H)2 / C (150 mg, 10%) and Pd / C (150 mg, 10%) in THF (20 mL) was stirred at room temperature overnight under hydrogen atmosphere by using H2 balloon. Then the mixture was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by Prep-HPLC [with the following conditions (Column: Atlantis Prep T3 OBD Column, 19* 150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 50 mL / min; Gradient: 3% B to 12% B in 8 min, 12% B; Wave Length: 254 / 220 nm; RTl(min): 4.81)] to afford the title product as a white solid (320 mg, 55.9%). LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 254.0 [M+H]+; 1H NMR (400 MHz, Deuterium Oxide) 57.38

[0115] (d, 7 = 7.4 Hz, 1H), 7.24 (t, 7 = 6.9 Hz, 1H), 5.00 (s, 2H), 3.93 (dd, 7 = 7.6, 5.7 Hz, 1H), 3.30 (dd,

[0116] 7= 14.5, 5.8 Hz, 1H), 3.11 (dd, 7 = 14.5, 7.7 Hz, 1H).

[0117] Preparation of Compound 7 aReagents and Conditions: (a) NBS, AIBN, MeCN, 80 °C; (b) DMSO, H2O, O2, 55 °C; (c) HCl, DHP, rt; (d) (1) B2Pin2, Pd(dppf)Cl2, AcOK, dioxane, 80 °C, (2) HCl, MeOH, rt; (e) HBr, rt; (f) NaHMDS, HMPA, THF, -78 °C; (g) (1) TFA, DCM, rt, (2) H2, Pd / C, Pd(OH)2 / C, THF, rt.

[0118] Preparation of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (7-1)

[0119] A solution of 1-bromo-4-fluoro-2,3-dimethylbenzene (5 g, 24.6 mmol, 1 equiv), NBS (9.20 g, 51.7 mmol, 2.1 equiv) and AIBN (0.40 g, 2.5 mmol, 0.1 equiv) in MeCN (50 mL) was stirred under nitrogen atmosphere at 80 °C for overnight. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. GCMS (El): mass calcd. for C8H6Br3F, 359.8; m / z found, 359.8 [M],

[0120] Preparation of [6-bromo-3-fluoro-2-(hydroxymethyl)phenyl]methanol (7-2)

[0121] A mixture of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (8.9 g, 24.7 mmol, 1 equiv) in DMSO (50 mL) and H2O (25 mL) was stirred at 55 °C for overnight under O2atmosphere by using oxygen balloon. Then the mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 60% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (4.9 g, 84.5%). LCMS (ESI): mass calcd. for C8H8BrFO2, 233.97; m / z found, 233 [M-H]-.

[0122] Preparation of 2-({3-bromo-6-fluoro-2-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (7-3)

[0123] A mixture of [6-bromo-3-fluoro-2-(hydroxymethyl)phenyl]methanol (4.9 g, 20.8 mmol, 1 equiv) and cone. HCl (1.5 mL) in DHP (80 mL) was stirred at room temperature for overnight. The raction was quenched with saturated NaHCCh (aq.). The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 100% gradient in 10 min; detector, UV 254 / 220 nm] to give the title product as a light yellow solid (7 g, 83.2%). LCMS (ESI): mass calcd. for Ci8H24BrFO4, 402.08; m / z found, 425.2 [M+Na]+.

[0124] Preparation of 5-fluoro-4-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (7-4)

[0125] Step A: A mixture of 2-({6-bromo-3-fluoro-2-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (7 g, 17.4 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (7.49 g, 29.5 mmol, 1.7 equiv), Pd(dppf)Cl2(0.64 g, 0.87 mmol, 0.05 equiv) and AcOK (3.92 g, 39.9 mmol, 2.3 equiv) in dioxane (70 mL) was stirred under nitrogen atmosphere at 80 °C for overnight. The resulting mixture was filtered, and the solid was washed with EtOAc (2x10 mL). The combined filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0126] Step B: A mixture of 2-{4-fluoro-2,3-bis[(oxan-2-yloxy)methyl]phenyl}-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (8 g, crude, 1 equiv) and 6 M HCl (aq., 10 mL) in MeOH (40 mL) was stirred at room temperature for 3 h. Then the mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 30% to 60% gradient in 10 min; detector, UV 220 nm] to afford the title product as a white solid (2.5 g, 77.3%). LCMS (ESI): mass calcd. for C8H8BFO3, 182.06; m / z found, 180.8[M-H]-.

[0127] Preparation of ethyl (2S)-2-amino-3-( 1-hydroxy-3H-2,1-benzoxaborol-6-yl)propanoate (7-5) A solution of 5-fluoro-4-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (2.5 g, 13.7 mmol, 1 equiv) in HBr (48% in water, 20 mL) was stirred at room temperature for overnight. The resulting mixture was diluted with water (50mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TEA), 40% to 70% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (2.2 g, 65.4%). LCMS (ESI): mass calcd. for C8H7BBrFO2, 243.97; m / z found, 242.9[M-H]-

[0128] Preparation of ethyl (2S)-2-amino-3-( 1-hydroxy-3H-2,1-benzoxaborol-6-yl)propanoate (7-6) To a stirred mixture of 4-(bromomethyl)-5-fluoro-3H-2,1-benzoxaborol-1-ol (1.3 g, 5.3 mmol, 1 equiv) and tert-butyl (2R,3S)-6-oxo-2,3-diphenylmorpholine-4-carboxylate (2.25 g, 6.4 mmol, 1.2 equiv) in HMPA (5 mL) and THE (20 mL) under nitrogen atmosphere at -78 °C was added NaHMDS (6.6 mL, 2.5 equiv, 2 mol / L) dropwise. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction was quenched with sat. NH4CI (aq.). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 50% to 90% gradient in 10 min; detector, UV 220 nm] to afford the title product (1.9 g, 69.1%) as a light yellow solid. LCMS (ESI): mass calcd. for C29H29BFNO6, 517.21; m / z found, 418 [M+H-Boc]+.

[0129] Preparation of 2-amino-3-(5-fluoro-1-hydroxy-3H-2,1-benzoxaborol-4-yl)propanoic acid (7) Step A: To a stirred solution of tert-butyl (5S,6R)-3-[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborol- 4-yl)methyl]-5,6-dimethyl-2-oxomorpholine-4-carboxylate (1 g, 2.54 mmol, 1 equiv) in DCM (15 mL) was added TEA (5 mL) slowly. The resulting mixture was stirred at room temperature for 3 h. Then the mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0130] Step B: A mixture of (3S,5S,6R)-3-((5-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)methyl)-5,6-diphenylmorpholin-2-one (1.1 g, crude), Pd(OH)2 / C (0.1 g, 10%) and Pd / C (0.1 g, 10%) in THF (10 mL) was stirred at room temperature for overnight under H2atmosphere by using hydrogen balloon. Then the mixture was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by Prep-HPLC [with the following conditions (Column: Atlantis Prep T3 OBD Column, 19* 150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 14% B in 10 min, 14% B; Wave Length: 220 / 200 nm; RTl(min): 8.32;)] to afford the title product (100 mg, 16.4%) as a white solid.

[0131] LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240.15 [M+H]+.1H NMR (400 MHz, Deuterium Oxide) 5 7.59 (dd, 7 = 8.1, 5.3 Hz, 1H), 7.11 (dd, 7 = 10.7, 8.1 Hz, 1H), 5.07- 4.95 (m, 2H), 3.87 (t, 7 = 7.2 Hz, 1H), 3.18-3.08 (m, 1H), 3.08- 2.99 (m, 1H).

[0132] Preparation of Compound 8

[0133] Reagents and Conditions: (a) H2O2(30%), NaOH, MeOH, 0 °C; (b) NBS, AIBN, MeCN, 80 °C; (c) DMSO, H2O, O2, 50 °C; (d) BH3-THF, THF, 50 °C; (e) DHP, HCl, rt; (f) Pd(dppf)Cl2, AcOK, dioxane, 80 °C; (g) HCl, rt; (h) 48% HBr in H2O, rt; (i) NaHMDS, HMPA, THF, -78 °C; (j) TFA, DCM, rt; (k) Pd / C, Pd(OH)2 / C, MeOH, rt.

[0134] Preparation of 5-bromo-2-fluoro-4-methylbenzoic acid (8-1) To a stirred mixture of 5-bromo-2-fluoro-4-methylbenzaldehyde (5 g, 23.04 mmol, 1 equiv) in MeOH (40 mL) at 0 °C was added NaOH (aq. 20 mL, 0.5 mol / L) slowly, followed by the addition of H2O2(40 mL, 30%) dropwise. The resulting mixture was stirred at room temperature for 5 h. Then the mixture was acidified to “pH” 4 with 2 N HCl at 0 °C, and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2CI2 / MeOH (5:1) to give the title product as a light yellow solid (4.8 g, 89.4%). LCMS (ESI): mass calcd. for C8H6BrFO2, 231.95; m / z found, 231.0 [M-H]-.

[0135] Preparation of 5-bromo-4-(bromomethyl)-2-fluorobenzoic acid (8-2)

[0136] To a stirred mixture of 5-bromo-2-fluoro-4-methylbenzoic acid (3.2 g, 13.73 mmol, 1 equiv) in MeCN (60 mL) were added AIBN (0.11 g, 0.69 mmol, 0.05 equiv) and NBS (2.44 g, 13.73 mmol, 1 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C for overnight. Then the mixture was concentrated, diluted with water (40 mL), and extracted with EtOAc (3 x 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (9: 1) to give the title product as a light yellow solid (2.1 g, 49.0%). LCMS (ESI): mass calcd. for C8H5Br2FO2, 309.86; m / z found, 310.9 [M+H]+.

[0137] Preparation of 5-bromo-2-fluoro-4-(hydroxymethyl)benzoic acid (8-3)

[0138] A solution of 5-bromo-4-(bromomethyl)-2-fluorobenzoic acid (2.7 g, 8.66 mmol, 1 equiv) in DMSO / H2O (15 mL / 7.5 mL) was stirred at 50 °C for overnight under O2atmosphere by using oxygen balloon. Then the mixture was diluted with water (20 mL), and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3 x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 50% gradient in 35 min; detector, UV 220 nm] to give the title product as a light yellow solid (2 g, 92.8%). LCMS (ESI): mass calcd. for C8H6BrFO3, 247.95; m / z found, 246.9 [M-H]".

[0139] Preparation of [5-bromo-2-fluoro-4-(hydroxymethyl)phenyl]methanol (8-4)

[0140] To a stirred mixture of 5-bromo-2-fluoro-4-(hydroxymethyl)benzoic acid (2 g, 8.03 mmol, 1 equiv) in THE (10 mL) under nitrogen atmosphere at 0 °C was added BH3-THF (24.1 mL, 24.09 mmol, 3.00 equiv, 1 mol / L in THE) drop wise. The resulting mixture was stirred under nitrogen atmosphere at 50 °C for overnight. The reaction was quenched with MeOH at 0 °C. The mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 65% gradient in 30 min; detector, UV 220 nm] to give the title product as an off-white solid (1.78 g, 94.3%).1H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J = 6.8 Hz, 1H), 7.25 (d, 7 = 10.9 Hz, 1H), 5.57 (t, 7 = 5.5 Hz, 1H), 5.37 (t, 7 = 5.9 Hz, 1H), 4.53 (s, 2H), 4.50 - 4.44 (m, 2H).

[0141] Preparation of 2-({2-bromo-5-fluoro-4-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (8-5)

[0142] To a stirred mixture of [5-bromo-2-fluoro-4-(hydroxymethyl)phenyl]methanol (1.78 g, 7.57 mmol, 1 equiv) in DHP (35 mL) was added cone. HCl (100 uL, 12 mol / L). The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 80% gradient in 15 min; detector, UV 220 nm] to give the title product as a light yellow oil (2.6 g, 85.1%). LCMS (ESI): mass ealed. for C18H24BrFO4, 402.08; m / z found, 420.2 [M+NH4]+.

[0143] Preparation of 4-fluoro-2,5-bis[(oxan-2-yloxy)methyl]phenylboronic acid (8-6)

[0144] To a stirred mixture of 2-({2-bromo-5-fluoro-4-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (2.6 g, 6.45 mmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2- dioxaborinane (2.18 g, 9.67 mmol, 1.5 equiv) in dioxane (50 mL) were added Pd(dppf)Ch (0.47 g, 0.65 mmol, 0.1 equiv) and AcOK (1.27 g, 12.89 mmol, 2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for overnight. Then the mixture was filtered. The filtrate was concentrated, diluted with water (80 mL), and extracted with EtOAc (3 x 80 mL). The combined organic layers were washed with brine (1x60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with PE / EA (1:1) to give the title product as a light yellow solid (2 g, 84.3%). LCMS (ESI): mass ealed. for C18H26BFO6, 368.18; m / z found, 367.05 [M-H]-.

[0145] Preparation of 5-fluoro-6-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (8-7)

[0146] A solution of 4-fluoro-2,5-bis[(oxan-2-yloxy)methyl]phenylboronic acid (2.2 g, 5.98 mmol, 1 equiv) in HCl (45 mL, 6 mol / L) was stirred at room temperature for 2 h. Then the mixture was diluted with water (40 mL), and extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 60% gradient in 30 min; detector, UV 220 nm] to give the title product as a white solid (1 g, 92.0%). LCMS (ESI): mass calcd. for C8H8BFO3, 182.06; m / z found, 181.00 [M-H]. Preparation of 6-(bromomethyl)-5-fluoro-3H-2,1-benzoxaborol-1-ol (8-8)

[0147] A mixture of 5-fluoro-6-(hydroxymethyl)-3H-2,1-benzoxaborol-1-ol (1 g, 5.496 mmol, 1 equiv) in HBr (20 mL, 48% in water) was stirred at room temperature for overnight. Then the mixture was diluted with water (50 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 60% gradient in 20 min; detector, UV 220 nm] to provide the title product as a light yellow solid (1.1 g, 81.8%). LCMS (ESI): mass calcd. for C8H7BBrFO2, 243.97; m / z found, 242.9 [M-H]-.

[0148] Preparation of tert-butyl (3S,5S,6R)-3-[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (8-9)

[0149] To a stirred mixture of 6-(bromomethyl)-5-fluoro-3H-2,1-benzoxaborol-1-ol (1.1 g, 4.49 mmol, 1 equiv) and tert-butyl (2R,3S)-6-oxo-2,3-diphenylmorpholine-4-carboxylate (2.38 g, 6.74 mmol, 1.5 equiv) in THE (20 mL) / HMPA (2 mL) under nitrogen atmosphere at -78 °C was added NaHMDS (3.4 mL, 2 mol / L in THE, 1.5 equiv) dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 2 h and at room temperature for 2 h. The reaction was quenched with sat. NH4CI (aq.). The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 20% to 80% gradient in 15 min; detector, UV 220 nm] to afford the title product as a light yellow solid (1.1 g, 47.3%). LCMS (ESI): mass calcd. for C29H29BFNO6, 517.21; m / z found, 418.20 [M- Boc+H]+.

[0150] Preparation of (3S,5S,6R)-3-[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)methyl]-5,6- diphenylmorpholin-2-one (8-10) To a stirred mixture of tert-butyl (3S,5S,6R)-3-[(5-fluoro- 1 -hydroxy-3 H-2, 1 -benzoxaborol-6- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (1 g, 1.93 mmol, 1 equiv) in DCM (3 mL) was added TFA (5 mL) slowly. The resulting mixture was stirred at room temperature for 2 h and then concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C24H21BFNO4, 417.15; m / z found, 418.20 [M+H].

[0151] Preparation of (2S)-2-amino-3-(5-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)propanoic acid (8)

[0152] To a stirred mixture of (3S,5S,6R)-3-[(5-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)methyl]- 5,6-diphenylmorpholin-2-one (870 mg, 2.09 mmol, 1 equiv) in MeOH (15 mL) were added Pd / C (87 mg, 10%) and Pd(OH)2 / C (87 mg, 10%). The resulting mixture was stirred at room temperature for overnight under H2atmosphere by using hydrogen balloon. Then the mixture was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by Prep-HPLC [with the following conditions : Column: Atlantis Prep T3 OBD Column, 19* 150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: isocratic 0% B to 8% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 10.55] to afford the title product as a white solid (150 mg, 29.9%). LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240.15 [M+H]+.1H NMR (400 MHz, Deuterium Oxide) 57.53 (d, 7= 7.6 Hz, 1H), 7.12 (d, 7 = 10.4 Hz, 1H), 4.94 (s, 2H), 3.93 (dd, 7= 7.7, 5.7 Hz, 1H), 3.30 (dd, 7= 14.6, 5.6 Hz, 1H), 3.09 (dd, 7= 14.6, 7.7 Hz, 1H).

[0153] Preparation of Compound 9 Reagents and Conditions: (a) NBS, AIBN, MeCN, 80 °C; (b) DMSO, H2O, O2, 50 °C; (c) BH3- THF, THF, 50 °C; (d) DHP, HCl, rt; (e) Pd(dppf)Cl2, AcOK, dioxane, 80oC; (f) HCl (aq.), rt; (g) 48% HBr in H2O, rt; (h) NaHMDS, HMPA, THF, -78oC; (i) TFA, DCM, rt; (j) Pd / C, Pd(OH)2 / C, MeOH, rt. Preparation of 3-bromo-4-(bromomethyl)-5-fluorobenzoic acid (9-1) A mixture of 3-bromo-5-fluoro-4-methylbenzoic acid (5 g, 21.46 mmol, 1 equiv), AIBN (0.18 g, 1.073 mmol, 0.05 equiv) and NBS (3.82 g, 21.46 mmol, 1 equiv) in MeCN (100 mL) was stirred under nitrogen atmosphere at 80 °C for overnight. The reaction was quenched with water (40 mL). The mixture was concentrated, and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with CH2Cl2 / MeOH (10:1) to give the title product as a light yellow solid (5 g, 74.7%). LCMS (ESI): mass calcd. For C8H5Br2FO2, 309.86; m / z found, 309 [M-H]".

[0154] Preparation of 3-bromo-5-fluoro-4-(hydroxymethyl)benzoic acid (9-2)

[0155] A solution of 3-bromo-4-(bromomethyl)-5-fluorobenzoic acid (5 g, 16.03 mmol, 1 equiv) in DMSO / H2O (20 mE / 10 mL) was stirred at 50 °C overnight under oxygen atmosphere by using O2balloon. Then the mixture was concentrated under vacuum. The residue was purified by reversed- phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 45% gradient in 30 min; detector, UV 220 nm] to provide the title product as a light yellow solid (3.9 g, 97.7%). LCMS (ESI): mass calcd. For C8H6BrFO3, 247.95; m / z found, 247.1 [M-H]-.

[0156] Preparation of [3-bromo-5-fluoro-4-(hydroxymethyl)phenyl]methanol (9-3)

[0157] To a stirred solution of 3-bromo-5-fluoro-4-(hydroxymethyl)benzoic acid (3.94 g, 15.82 mmol, 1 equiv) in THF (20 mL) at 0 °C was added BH3-THF (47.46 mL, 1 mol / L in THF, 3.00 equiv) dropwise. The resulting mixture was stirred under nitrogen atmosphere at 50 °C overnight. The reaction was quenched with MeOH at 0 °C. The mixture was concentrated under vacuum. The residue was purified by re versed-phase flash chromatography [with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 60% gradient in 40 min; detector, UV 220 nm] to give the title product as a white solid (3.5 g, 94.1%).1H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.36 (m, 1H), 7.16 - 7.08 (m, 1H), 4.54 (d, 7 = 2.2 Hz, 2H), 4.47 (s, 2H).

[0158] Preparation of 2-({2-bromo-5-fluoro-4-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (9-4)

[0159] To a stirred mixture of [5-bromo-2-fluoro-4-(hydroxymethyl)phenyl]methanol (1.04 g, 4.425 mmol, 1 equiv) in DHP (20 mL) was added cone. HCl (100 uL, 12 mol / F). The resulting mixture was stirred at room temperature overnight. Then the mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 90% gradient in 40 min; detector, UV 220 nm] to afford the title product as a light yellow oil (1 g, 56.0%). LCMS (ESI): mass calcd. For C18H24BrFO4, 402.08; m / z found, 419.9 [M+NH4]+.

[0160] Preparation of 3-fluoro-2,5-bis[(oxan-2-yloxy)methyl]phenylboronic acid (9-5)

[0161] To a stirred mixture of 2-({2-bromo-6-fluoro-4-[(oxan-2-yloxy)methyl]phenyl}methoxy)oxane (1 g, 2.48 mmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-l,3,2- dioxaborinane (0.84 g, 3.72 mmol, 1.5 equiv) in dioxane (20 mL) were added Pd(dppf)Cl2(0.18 g, 0.25 mmol, 0.1 equiv) andAcOK (0.49 g, 4.96 mmol, 2 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C. The reaction was quenched by the addition of water (40 mL). The mixture was concentrated, and extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine (lx 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 90% gradient in 40 min; detector, UV 220 nm] to give the title product as a light yellow solid (800 mg, 87.6%). LCMS (ESI): mass calcd. For C18H26BFO6, 368.18; m / z found, 367.1 [M- H].

[0162] Preparation of 4-fluoro-6-(hydroxymethyl)-3H-2,1-benzoxaborol-l-ol (9-6)

[0163] A mixture of 3-fluoro-2,5-bis[(oxan-2-yloxy)methyl]phenylboronic acid (493 mg, 1.34 mmol, 1 equiv) in HCl (10 mL, 6 mol / L) was stirred at room temperature for 2 h. Then the mixture was diluted with water (10 mL), and extracted with EtOAc (4 x 15 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 50% gradient in 30 min; detector, UV 220 nm] to afford the title product as a white solid (180 mg, 73.9%).1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.52 (s, 1H), 7.20 (dd, 7 = 10.5, 1.1 Hz, 1H), 5.33 (t, 7 = 5.7 Hz, 1H), 5.05 (s, 2H), 4.55 (d, 7= 5.7 Hz, 2H).

[0164] Preparation of 6-(bromomethyl)-4-fluoro-3H-2,1-benzoxaborol-1-ol (9-7)

[0165] A mixture of 4-fluoro-6-(hydroxymethyl)-3H-2,1-benzoxaborol-l-ol (1.7 g, 9.34 mmol, 1 equiv) in HBr (48% in water, 20 mL) was stirred at room temperature for overnight. Then the mixture was diluted with water (30 mL), and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 80% gradient in 40 min; detector, UV 220 nm] to give the title product as a yellow solid (998 mg, 43.6%). LCMS (ESI): mass calcd. For C8H7BbrFO2, 243.97; m / z found, 242.85 [M-H]-.

[0166] Preparation of tert-butyl (3S,5S,6R)-3-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (9-8) To a stirred mixture of 6-(bromomethyl)-4-fluoro-3H-2,1-benzoxaborol-l-ol (1 g, 4.08 mmol, 1 equiv) and tert-butyl (2R,3.S')-6-oxo-2,3-diphenylmorpholine-4-carboxylate (2.17 g, 6.13 mmol, 1.5 equiv) in THF (20 mL) / HMPA (2 mL) under nitrogen atmosphere at -78 °C was added NaHMDS (6.13 mL, 1 mol / L in THE 1.50 equiv) dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 2 h, then at room temperature for 2 h. The reaction was quenched with sat. NH4CI (aq.). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 40 min; detector, UV 220 nm] to afford the title product as a light yellow solid (1.2 g, 56.8%). LCMS (ESI): mass calcd. For C29H29BFNO6, 517.21; m / z found, 418.25 [M- Boc+H]+.

[0167] Preparation of (3S,5S,6R)-3-[(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)methyl]-5,6- diphenylmorpholin-2-one (9-9)

[0168] To a stirred mixture of tert-butyl (3S,5S,6R)-3-[(4-fluoro- 1 -hydroxy-3 H-2, 1 -benzoxaborol-6- yl)methyl]-2-oxo-5,6-diphenylmorpholine-4-carboxylate (1.2 g, 2.32 mmol, 1 equiv) in DCM (15 mL) was added TFA (5 mL) slowly. The resulting mixture was stirred at room temperature for 2 h. Then the mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. For C24H21BFNO4, 417.15; m / z found, 418.25 [M+H],

[0169] Preparation of (2S)-2-amino-3-(4-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl)propanoic acid (9)

[0170] To a stirred mixture of (3S,5S,6R)-3-[(4-fluoro- 1 -hydroxy-3H-2, 1 -benzoxaborol-6-yl)methyl]- 5,6-diphenylmorpholin-2-one (900 mg, 2.16 mmol, 1 equiv) in MeOH (20 mL) were added Pd / C (90 mg, 10%) and Pd(OH)2 / C (90 mg, 10%). The resulting mixture was stirred at room temperature overnight under hydrogen atmosphere by using H2balloon. Then the mixture was filtered through a pad of Celite. The filtrate was concentrated and the residue was purified by Prep-HPLC [with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 10% B in 8 min; Wave Length: 254 nm / 220 nm; RT1 (min): 4.27)] to afford the title product as a white solid (56 mg, 10.8%). LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240.15 [M+H].1H NMR (400 MHz, Deuterium Oxide) 7.31 (s, 1H), 7.07 (dd, J = 10.5, 1.4 Hz, 1H), 5.00 (s, 2H), 3.93 (dd, J = 7.7, 5.4 Hz, 1H), 3.24 (dd, J = 14.5, 5.4 Hz, 1H), 3.11 (dd, J = 14.5, 7.7 Hz, 1H). Preparation of Compound 10 aReagents and Conditions: (a) B(OiPr)3, n-BuLi, THF, Toluene, -78oC, r.t.; (b) pinacol, MgSO4, Et2O, r.t.; (c) Zn, I2, Pd2(dba)3, S-phos, DMF, 50oC; (d) NBS, AIBN, CCl4, 80oC; can NaCN, DMSO, 40oC; (f) Raney Ni, MeOH, r.t.; (g) LiOH·H2O, THF, H2O, r.t.; (h) 4M HCl in dioxane, rt. Preparation of 3-bromo-2-methylphenylboronic acid (10-1) To a stirred mixture of 1,3-dibromo-2-methylbenzene (10 g, 40.011 mmol, 1 equiv) in THF (40 mL) and toluene (160 mL) at -78 °C was added n-BuLi (19.21 mL, 48.013 mmol, 1.20 equiv, 2.5 M in hexane) dropwise. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 30 min. To the above mixture at -78 °C was added B(OiPr)3(9.23 mL, 40.011 mmol, 1 equiv) dropwise. The resulting mixture was stirred at -78 °C for 2 h and at room temperature for 2 h. The reaction was quenched by the addition of 2 M HCl (aq.) (40 mL), and stirred at room temperature for 30 min. The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 30% gradient in 20 min; detector, UV 220 nm] to afford the title product as a white solid (7.6 g, 88.41%). LCMS (ESI): mass calcd. for C7h8BBrO2, 213.98; m / z found, 212.80 [M-H]-.

[0171] Preparation of 2-(3-bromo-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10-2) A mixture of 3-bromo-2-methylphenylboronic acid (7.4 g, 34.443 mmol, 1 equiv), pinacol (4.88 g, 41.332 mmol, 1.2 equiv) and MgSO4(8.29 g, 68.886 mmol, 2 equiv) in Et2O (150 mL) was stirred under nitrogen atmosphere at room temperature for 3 h. The mixture was concentrated and purified by silica gel column chromatography [eluted with PE / EA (10: 1)] to afford the title product as an off-white solid (8.3 g, 81.14%). LCMS (ESI): mass calcd. For C13H18BbrO2, 296.06; m / z found, 297.25 [M+H]+.

[0172] Preparation of methyl (S)-2-[(tert-butoxycarbonyl) amino]-3-[2-methyl-3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (10-3)

[0173] A mixture of Zn (3.70 g, 56.564 mmol, 4 equiv) and I2 (0.36 g, 1.414 mmol, 0.1 equiv) in DMF (20 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2- [(tert-butoxycarbonyl) amino]-3-iodopropanoate (9.31 g, 28.282 mmol, 2 equiv) in DMF (10 mL) and I2(0.36 g, 1.414 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for additional 30 min. To the above mixture was added a solution of 2-(3-bromo-2- methylphenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (4.2 g, 14.141 mmol, 1 equiv) in DMF (10 mL), Pd2(dba)3(1.29 g, 1.414 mmol, 0.1 equiv) and S-Phos (0.87 g, 2.121 mmol, 0.15 equiv). The resulting mixture was stirred under nitrogen atmosphere at 50 °C overnight. The reaction was quenched with Water (50 mL) at room temperature. The resulting mixture was filtered, the filter cake was washed with EtOAc (1 x 50 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 40% gradient in 20 min; detector, UV 220 nm] to afford the title product as an off-white solid (3.8 g, 64.08%). LCMS (ESI): mass calcd. for C22H34BNO6, 419.25; m / z found, 320.30 [M-Boc+H]+.

[0174] Preparation of methyl (S)-3-[2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]-2-[(tert-butoxycarbonyl) amino] propanoate (10-4)

[0175] A mixture of methyl (S)-2-[(tert-butoxycarbonyl) amino]-3-[2-methyl-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] propanoate (3.8 g, 9.062 mmol, 1 equiv), NBS (1.77 g, 9.968 mmol, 1.1 equiv) and AIBN (0.15 g, 0.906 mmol, 0.1 equiv) in CCI4(40 mL) was stirred under nitrogen atmosphere at 80 °C overnight. The resulting mixture was concentrated and purified by silica gel column chromatography [eluted with PE / EA (10: 1)] to afford the title product as a yellow oil (2.0 g, 44.30%). LCMS (ESI): mass calcd. for C22H33BBrNO6, 499.16; m / z found, 400.15 [M-Boc+H]+.

[0176] Preparation of methyl (S)-2-[(tert-butoxycarbonyl) amino]-3-[2-(cyanomethyl)-3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] propanoate (10-5)

[0177] A mixture of methyl (S)-3-[2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2- [(tert-butoxycarbonyl)amino]propanoate (2 g, 4.014 mmol, 1 equiv) and NaCN (0.35 g, 7.225 mmol, 1.8 equiv) in DMSO (20 mL) was stirred under nitrogen atmosphere at 40 °C for 2 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 70% gradient in 10 min; detector, UV 220 nm] to afford the title product as a yellow oil (900 mg, 50.46%). LCMS (ESI): mass calcd. For C23H33BN2O6, 444.24; m / z found, 345.25 [M-Boc+H]+.

[0178] Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-1, 2,3,4- tetrahydrobenzo[c] [1,2]azaborinin-5-yl)propanoate (10-6)

[0179] A mixture of methyl (S)-2-[(tert-butoxycarbonyl) amino]-3-[2-(cyanomethyl)-3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] propanoate (900 mg, 2.025 mmol, 1 equiv) and Raney Ni (173.53 mg, 2.025 mmol, 1 equiv) in MeOH (10 mL) was stirred under hydrogen atmosphere at room temperature overnight. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 40% gradient in 10 min; detector, UV 220 nm] to give the title product as a light yellow solid (420 mg, 59.55%). LCMS (ESI): mass calcd. for C17H25BN2O5, 348.19; m / z found, 367.20 [M+18+H]+;

[0180] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-1,2,3,4-tetrahydrobenzo [c][1,2]azaborinin-5-yl)propanoic acid (10-7)

[0181] A mixture of methyl methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1 -hydroxy- 1, 2,3,4- tetrahydrobenzo[c][1,2]azaborinin-5-yl)propanoate (420 mg, 1.206 mmol, 1 equiv) and LiOH· H2O (151.83 mg, 3.618 mmol, 3 equiv) in THF (3 mL) and H2O (3 mL) was stirred under nitrogen atmosphere at room temperature for 3 h. The mixture was acidified to “pH” 6 with 2 M HCl (aq.), diluted with water (10 mL), and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 30% gradient in 10 min; detector, UV 220 nm] to afford the title product as an off-white solid (230 mg, 57.06%). LCMS (ESI): mass calcd. for C16H23BN2O5, 334.17; m / z found, 352.95 [M+18+H]+.

[0182] Preparation of (S)-2-amino-3-(1-hydroxy-l,2,3,4-tetrahydrobenzo[c][l,2]azaborinin-5- yl)propanoic acid (10)

[0183] To a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(1 -hydroxy- 1,2, 3,4- tetrahydrobenzo[c][1,2]azaborinin-5-yl)propanoic acid (230 mg, 0.688 mmol, 1 equiv) in 1,4- dioxane (2 mL) was added 2M HCl (2 mL, in 1 ,4-dioxane) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 3 h. The mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC [with the following conditions (Column: XB ridge Prep Amide OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 88% B to 68% B in 8 min; Wave Length: 254 nm / 220 nm; RT1 (min): 7.07)] to afford the title product as a light yellow solid (104 mg, 64.56%). LCMS (ESI): mass calcd. for C11H15BN2O3, 234.12; m / z found, 253.10 [M+18+H]+.1H NMR (400 MHz, Deuterium Oxide): δ 7.42 (dd, 7 = 5.8, 3.0 Hz, 1H), 7.32 - 7.22 (m, 2H), 4.02 (dd, 7 = 8.8, 6.2 Hz, 1H), 3.34 (dd, 7= 14.8, 6.2 Hz, 1H), 3.18 - 2.95 (m, 5H). Preparation of Compound 11 aReagents and Conditions: (a) NH3in dioxane, 40 °C, r.t.; (b) LiOH· H2O, THF, H2O, r.t.; (h) 4 M HCl in 1,4-dioxane, r.t.

[0184] Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-2,3-dihydro-1H- benzo[c] [1,2]azaborol-4-yl)propanoate (11-1)

[0185] A mixture of methyl (2S)-3-[2-(bromomethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -2- [(tert-butoxycarbonyl)amino]propanoate (2.208 mmol, 1 equiv) in 0.4 M NH3(10 mL, in dioxane) was stirred under nitrogen atmosphere at 40 °C for 2 h. The mixture was acidified to “pH” 3 with 2 M HCl (aq.) and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 5% to 50% gradient in 10 min; detector, UV 254 nm] to afford the title product as an off-white solid (350 mg, 47.44%). LCMS (ESI): mass calcd. for C16H23BN2O5, 334.17; m / z found, 253.00 [M-Boc+H2O+H]+.

[0186] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-2,3-dihydro-1H- benzo[c][1,2]azaborol-4-yl)propanoic acid (11-2)

[0187] A mixture of methyl methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-2,3-dihydro-1H- benzo[c][1,2]azaborol-4-yl)propanoate (450 mg, 1.347 mmol, 1 equiv) and LiOH· H2O (113.00 mg, 2.694 mmol, 2 equiv) in THF (4 mL) and H2O (4 mL) was stirred under nitrogen atmosphere at room temperature for 3 h. The mixture was acidified to “pH” 5 with 2 M HCl (aq.) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title product as a brown solid (255 mg, crude). LCMS (ESI): mass calcd. for C15H21BN2O5, 320.15; m / z found, 220.95 [M-Boc+H]+.

[0188] Preparation of (S)-2-amino-3-(1-hydroxy-2,3-dihydro-1H-benzo[c][1,2]azaborol-4- yl)propanoic acid (11)

[0189] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-2,3-dihydro-1H- benzo[c][1,2]azaborol-4-yl)propanoic acid (255 mg, 0.797 mmol, 1 equiv) in 1,4-dioxane (2 mL) was added 4M HCl (2 mL, in 1 ,4-dioxane) slowly. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC [with the following conditions (Column: XBridge Prep Amide OBD Column, 19*150 mm, 5μm; Mobile Phase A: Water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: isocratic 95% B to 70% B in 10 min; Wave Length: 254 nm / 220 nm; RTl(min): 14.38] to afford the title product as a white solid (20.6 mg, 11.75%). LCMS (ESI): mass calcd. for C10H13BN2O3, 220.10; m / z found, 239.20 [M+H2O+H]+.1H NMR (400 MHz, Deuterium Oxide): δ 7.62 (d, J = 6.6 Hz, 1H), 7.36 (d, J = 6.4 Hz, 2H), 4.40 - 4.09 (m, 3H), 3.41 (dd, 7 = 15.0, 7.1 Hz, 1H), 3.22 (dd, 7= 15.1, 8.2 Hz, 1H).

[0190] Preparation of Compound 12 aReagents and Conditions: (a) Zn, I2, Pd2(dba)3, S-phos, DMF, 40 °C; (b) B2(neop)2, Pd2(dba)3, PCy3-HBF4, KOAc, dioxane, 80 °C; (c) LiOH·H2O, THF, H2O, rt; (d) 4M HCl in dioxane, dioxane, rt.

[0191] Preparation of ethyl 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2- chlorobenzoate (12-1)

[0192] A mixture of Zn (2.98 g, 45.54 mmol, 4 equiv) and I2(288.95 mg, 1.14 mmol, 0.1 equiv) in DMF (30 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (7.49 g, 22.77 mmol, 2 equiv) in DMF (15 mL) and I2 (288.95 mg, 1.14 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for additional 30 min. To the above mixture was added a solution of ethyl 5-bromo- 2-chlorobenzoate (3 g, 11.38 mmol, 1 equiv) in DMF (15 mL), Pd2(dba)3(1.04 g, 1.14 mmol, 0.1 equiv) and S-Phos (701.06 mg, 1.71 mmol, 0.15 equiv). The resulting mixture was stirred under nitrogen atmosphere at 40 °C overnight. The mixture was diluted with water (50 mL) and filtered; the filter cake was washed with EtOAc (3 x 10 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water (2x50 mL) and brine (1 x 50 mL), dried over anhydrous Na3SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 50% to 70% gradient in 10 min; detector, UV 220 nm] to give the title product (3.07 g, 69.89%). LCMS (ESI): mass calcd. for C18H24CINO6, 385.1; m / z found, 286.1 [M+H-Boc]+.

[0193] Preparation of (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2- (ethoxycarbonyl)phenyl)boronic acid (12-2)

[0194] To a stirred solution of ethyl 5-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-methoxy-3-oxopropyl]-2- chlorobenzoate (1.5 g, 3.89 mmol, 1 equiv) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5- dimethyl-1,3,2-dioxaborinane (1.76 g, 7.78 mmol, 2 equiv) in dioxane (30 mL) were added KOAc (1.14 g, 11.66 mmol, 3 equiv), Pd3(dba)3(356.00 mg, 0.39 mmol, 0.1 equiv) and PCy3.HBF4(286.32 mg, 0.78mmol, 0.2 equiv). The resulting mixture was stirred under nitrogen atmosphere at 80 °C overnight. The mixture was diluted with water (50 mL), and filtered, the filter cake was washed with EtOAc (10 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 220 nm] to give the title product (470 mg, 30.59%). LCMS (ESI): mass calcd. for C18H26BNO8, 395.2; m / z found, 418.3 [M+Na]+

[0195] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3-oxo-l,3- dihydrobenzo[c][1,2]oxaborol-5-yl)propanoic acid (12-3)

[0196] To a stirred mixture of (S)-(4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-2- (ethoxycarbonyl)phenyl)boronic acid (420 mg, 1.06 mmol, 1 equiv) in THE (8 mL) and H2O (4 mL) was added LiOH.H2O (133.77 mg, 3.19 mmol, 3 equiv). The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to pH 5 with 2N HCl (aq.) and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, Cl 8; mobile phase, MeCN in Water (0.1% FA), 0% to 10% gradient in 4 min; detector, UV 220 nm] to give the title product as a white solid (300 mg, 84.24%). LCMS (ESI): mass calcd. for C15H18BNO7, 335.1; m / z found, 277.2 [M+H+ACN-Boc]+.

[0197] Preparation of (S)-2-amino-3-(1-hydroxy-3-oxo-l,3-dihydrobenzo[c][1,2]oxaborol-5- yl)propanoic acid (12)

[0198] To a stirred mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3-oxo-l,3- dihydrobenzo[c][1,2]oxaborol-5-yl)propanoic acid (280 mg, 0.84 mmol, 1 equiv) in dioxane (6 mL) was added 4M HC1 (6 mL, in 1,4-dioxane). The resulting mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by trituration with acetonitrile (5 mL) to give the title product as a white solid (103.7 mg, 52.81%). LCMS (ESI): mass calcd. for C10H10BNO5, 235.1; m / z found, 236.1 [M+H]+. *H NMR (400 MHz, Deuterium Oxide) δ 7.57 - 7.45 (m, 2H), 7.40 (d, J = 7.4 Hz, 1H), 4.16 (dd, J = 7.9, 5.4 Hz, 1H), 3.31 (dd, J = 14.6, 5.4 Hz, 1H), 3.16 (dd, J = 14.6, 7.9 Hz, 1H). Preparation of Compounds 13a and 13b

[0199] Reagents and Conditions: (a) BH3·THF, THF, 50 °C; (b) DHP, TsOH·H2O, THF, DCM, rt;

[0200] (c)B2Pin2, Pd(dppf)Cl2, AcOK, dioxane, 80 °C; (e) HC1 (6M), MeOH, H2O, rt; (f) K2CO3, 18- crown-6, MeCN, rt; (g) LiOH·H2O, THF, H2O, rt;

[0201] Preparation of methyl (2-bromo-6-(hydroxymethyl)phenyl)methanol (13-1)

[0202] To a stirred solution of 3-bromobenzene-l,2-dicarboxylic acid (5 g, 20.4 mmol, 1 equiv) in THF

[0203] (100 mL) was added BH3·THF (61.2 ml, 61.2 mmol, 3 equiv, 1 mol / L) dropwise at 0 °C. The resulting mixture was stirred overnight at 50 °C. The reaction was quenched by the addition of MeOH (30 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10: 1) to afford (2-bromo-6-(hydroxymethyl)phenyl)methanol (2.8 g, 63.2%) as a light yellow solid. LCMS (ESI): mass calcd. for C8H9BrO2, 216.0; m / z found, 215.0 [M-H]".

[0204] Preparation of methyl 2-((3-bromo-2-((oxan-2-yloxy)methyl)phenyl)methoxy)oxane (13-2)

[0205] A mixture of (2-bromo-6-(hydroxymethyl)phenyl)methanol (3 g, 13.8 mmol, 1 equiv), DHP (3.49 g, 41.4 mmol, 3 equiv) and TsOH·H2O (0.16 g, 2.2 mmol, 0.16 equiv) in THF / DCM (30 mL / 15 mL) was stirred overnight at room temperature. Then the mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 100% gradient in 10 min; detector, UV 220 nm. This resulted in 2-((3-bromo-2-((oxan-2- yloxy)methyl)phenyl)methoxy)oxane (3.5 g, 65.7%) as a yellow liquid.

[0206] LCMS (ESI): mass calcd. for C18H25BrO4, 384.1; m / z found, 407.0 [M+Na]+.

[0207] Preparation of 2-(2,3-bis((oxan-2-yloxy)methyl)phenyl)-4,4,5,5-tetramethyl-l,3,2- dioxaborolane (13-3)

[0208] To a stirred mixture of 2-((3-bromo-2-((oxan-2-yloxy)methyl)phenyl)methoxy)oxane (4 g, 10.3 mmol, 1 equiv), bis(pinacolato)diboron (4.48 g, 17.6 mmol, 1.7 equiv) and KO Ac (2.34 g, 23.9 mmol, 2.3 equiv) in 1, 4-dioxane (30 mL) was added Pd(dppf)C2. CH2Cl2(0.85 g, 1.0 mmol, 0.1 equiv). The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. Then the reaction was quenched by the addition of water (50 mL) and the mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 100% gradient in 10 min; detector, UV 220 nm. This resulted in 2-(2,3-bis((oxan-2-yloxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (4 g, 89.1%) as a yellow oil. LCMS (ESI): mass calcd. for C24H37BO6, 432.3; m / z found, 455 [M+Na]+.

[0209] Preparation of 4-( hydroxymethyl)-3H-2,1-benzoxaborol- Lol (13-4)

[0210] To a stirred mixture of 2-(2,3-bis((oxan-2-yloxy)methyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (4 g, 9.2 mmol, 1 equiv) in MeOH (40 mL) was added 6 M HCl (aq.) (20 mL) slowly. The resulting mixture was stirred overnight at room temperature. The mixture was basified to pH 6 with 3 M NaOH (aq.), and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TEA), 10% to 50% gradient in 10 min; detector, UV 220 nm. This resulted in 4-(hydroxymethyl)-3H-2,1 -benzoxaborol- 1 -ol (2.7 g, 89.0%) as a white solid.1H NMR (300 MHz, Methanol-d4) δ 7.57 (d, 7 = 7.2 Hz, 1H), 7.43 (d, 7= 7.5, 1H), 7.33 (t, 7= 7.3 Hz, 1H), 5.14 (s, 2H), 4.62 (s, 2H).

[0211] Preparation of 4-(bromomethyl)-3H-2,1-benzoxaborol- 1 -ol (13-5)

[0212] A mixture of 4-(hydroxymethyl)-3H-2, 1 -benzoxaborol- l -ol (1.2 g, 7.3 mmol, 1 equiv) in HBr (12.00 mL, 48 wt. % in water) was stirred overnight at room temperature. The resulting mixture was diluted with water (20 mL). The precipitated solids were collected by filtration and washed with water (3x10 mL). The resulting solid was dried under vacuum. This resulted in 4- (bromomethyl)-3H-2,1-benzoxaborol-l-ol (1.1 g, 66.2%) as a white solid.1H NMR (300 MHz, Methanol-d4) δ 7.62 (d, J = 7.3 Hz, 1H), 7.46 (dd, J = 7.5, 1.1 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 5.19 (s, 2H), 4.58 (s, 2H).

[0213] Preparation of ethyl (2S)-2-amino-3-( 1-hydroxy-3H-2,1-benzoxaborol-4-yl)propanoate (13- 6a) and ethyl (2R)-2-amino-3-( 1-hydroxy -3 / / -2.1-benzoxaborol-4-yl)propanoate (13-6b)

[0214] A mixture of 4-(bromomethyl)-3H-2,1-benzoxaborol- l -ol (0.5 g, 2.2 mmol, 1 equiv), ethyl- 2- isocyanoacetate (0.30 g, 2.6 mmol, 1.2 equiv), 18-crown-6 (0.06 g, 0.22 mmol, 0.1 equiv) and K2CO3(0.91 g, 6.6 mmol, 3 equiv) in MeCN (5 mL) was stirred overnight at room temperature under nitrogen atmosphere. Then the mixture was filtered, the filter cake was washed with acetonitrile (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and EtOH (2 mL) and then cone. HCl (1 mL) was added slowly. The resulting mixture was stirred for 2 h at room temperature. The mixture was concentrated under reduced pressure, basified to pH 8 with 2 M NaOH(aq.), and purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 23% B in 7 min, 23% B; Wave Length: 254 / 220 nm; RTl(min): 6.88;) to afford ethyl 2-amino-3-(1-hydroxy-3H- 2,1-benzoxaborol-4-yl)propanoate (90 mg, 16.4%) as a light yellow oil. Then, the racemic product (90 mg) was separated by CHIRAL-HPLC with the following conditions (Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: Hex(10mM NH3-MeOH), Mobile Phase B: EtOH— HPLC; Flow rate: 20 mL / min; Gradient: 30% B to 30% B in 24 min; Wave Length: 203 / 220 nm; RTl(min): 7.625; RT2(min): 16.245; Sample Solvent: EtOH— HPLC; Injection Volume: 1.5 mL; Number Of Runs: 2) to afford ethyl (2S)-2-amino-3-(1-hydroxy-3H-2,1-benzoxaborol-4- yl)propanoate(17 mg, 37%, ee>99%, 1stisomer on HPLC) as a light yellow oil and ethyl (2R)-2- amino-3-(1-hydroxy-3H-2,1-benzoxaborol-4-yl)propanoate (13 mg, 28%, ee>99%, 2ndisomer on HPLC) as a light yellow oil. LCMS (ESI): mass ealed. for C12H16BNO4, 249.1; m / z found, 250.0 [M+H]+.

[0215] Preparation of (S)-2-amino-3-(l-hydroxy-l,3-dihydrobenzo[c][l,2]oxaborol-4-yl)propanoic acid (13a)

[0216] To a stirred solution of ethyl (2S)-2-amino-3-(1-hydroxy-3H-2,1-benzoxaborol-4-yl)propanoate (30 mg, 0.12 mmol, 1 equiv; 1stisomer on HPLC)) in MeOH (1 mL) and water (0.5 mL) was added LiOH·H2O (15 mg, 0.36 mmol, 3 equiv). The resulting mixture was stirred for 1 h at room temperature. Then the mixture was acidified to pH 5 with HCl (aq.) and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 20% B in 7 min, 20% B; Wave Length: 254 / 220 nm; RTl(min): 4.80) to afford (S)-2-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)propanoic acid (25 mg, 61.95%) as a white solid. LCMS (ESI): mass calcd. for C10H12BNO4, 221.1; m / z found, 222.0 [M+H]+,1H NMR (400 MHz, Deuterium Oxide) 5 7.67-7.52 (m, 1H), 7.41-7.26 (m, 2H), 5.09-4.96 (m, 2H), 4.13-3.96 (m, 1H), 3.19 (dd, 7 = 14.8, 6.3 Hz, 1H), 3.08- 2.94 (m, 1H).

[0217] Preparation of (R)-2-amino-3-(1-hydroxy-l,3-dihydrobenzo[c][1,2]oxaborol-4-yl)propanoic acid (13b).

[0218] To a stirred solution of ethyl (2R)-2-amino-3-(1-hydroxy-3H-2,1-benzoxaborol-4-yl)propanoate (30 mg, 0.12 mmol, 1 equiv; 2ndisomer on HPLC) in MeOH ( 1 mL) and water (0.5 mL) was added

[0219] LiOH·H2O (15 mg, 0.36 mmol, 3 equiv). The resulting mixture was stirred for 1 h at room temperature. Then the mixture was acidified to pH 5 with HCl (aq.) and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Column: YMC- Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 17% B in 7 min, 17% B; Wave Length: 254 / 220 nm; RTl(min): 5.68) to afford (R)-2-amino-3-(1 -hydroxy- 1,3-dihydrobenzo[c][1,2]oxaborol-4- yl)propanoic acid (14 mg, 34.7%) as a white solid. LCMS (ESI): mass calcd. for C10H12BNO4, 221.1; m / z found, 222.0 [M+H]+,1H NMR (400 MHz, Deuterium Oxide) 5 7.68-7.52 (m, 1H), 7.41-7.29 (m, 2H), 5.13-4.96 (m, 2H), 4.19-3.96 (m, 1H), 3.29-3.13 (m, 1H), 3.09-2.94 (m, 1H).

[0220] Preparation of Compound 14

[0221] Reagents and Conditions: (a) NBS, AIBN, CH3CN, 80 °C; (b) DMSO, H2O, O2, 50 °C; (c) BH3- THF, 50 °C; (d) DHP, HCl, r.t.; (e) B2Pin2, Pd(dppf)Cl2, AcOK, 90 °C; (f) 6 M HCl (aq.), r.t.; (g) HBr in H2O, 50 °C; (h) NaHMDS, HMPA, THF, -78 °C; (i) TFA, DCM, r.t.; (j) Pd / C, Pd(OH)2, THF, r.t.

[0222] Starting with 6-bromo-2,4-difluoro-3 -methylbenzoic acid and using essentially the synthetic procedures described for the synthesis Compound 6, steps a-1, the title compound was obtained. LCMS (ESI): mass calcd. for C10H10BF2NO4, 257.07; m / z found, 258.15 [M+H]+;1H NMR (400 MHz, Deuterium Oxide) δ 7.04 (d, J = 8.2 Hz, 1H), 4.83 (s, 2H), 4.13 (t, J = 6.9 Hz, 1H), 3.30 - 3.12 (m, 2H).

[0223] Preparation of Compound 15

[0224] Reagents and Conditions: (a) Br2, AgNO3, HNO3, AcOH, H2O, rt; (b) NBS, AIBN, ACN, 80 °C; (c) DMSO, H2O, O2, 50 °C; (d) BH3-THF(lM in THF), THF, 50 °C; (e) DHP, HCl, rt; (f) B2pin2, Pd(dppf)Cl2, AcOK, dioxane, 90 °C; (g) HCl(aq., 6M), MeOH, rt; (h) HBr(48% in water), 50 °C; (i) NaHMDS, HMPA, THF, -78 °C; (j) TFA, DCM, rt; (k) Pd / C, Pd(OH)2 / C, THF, rt.

[0225] Preparation of 5-bromo-2,3-difluoro-4-methylbenzoic acid (15-1)

[0226] To a stirred solution of 2,3-difluoro-4-methylbenzoic acid (5 g, 29.05 mmol, 1 equiv) in AcOH (100 mL) / H2O (40 mL) was added HNO3 (24.75 mL, 68%) slowly. To the mixture at 0 °C was added Br2(2.98 mL, 58.10 mmol, 2 equiv) and a solution of AgNO3(9.87 g, 58.10 mmol, 2 equiv) in H2O (40 mL) dropwise. The resulting mixture was stirred at room temperature overnight. Then the mixture was filtered, the solid was washed with EtOAc (3x10 mL). The filtrate was concentrated under vacuum, and diluted with EtOAc (150 mL). The mixture was washed with IM HCl (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10: 1) to give the title product as a yellow solid (6.35 g, crude). LCMS (ESI): mass calcd. for C8H5BrF2O2, 250.0; m / z found, 249.0 [M-H]-.

[0227] Preparation of (2S)-2-amino-3-(4,5-difluoro-1-hydroxy-3H-2,1-benzoxaborol-6- yl)propanoic acid (15)

[0228] Starting with intermediate 15-1 and using essentially the synthetic procedures described for the synthesis Compound 6, steps b-1, the title compound was obtained.

[0229] LCMS (ESI): mass calcd. for C10H10BF2NO4, 257.1; m / z found, 258.0 [M+H]+.1H NMR (400 MHz, Deuterium Oxide) δ 6.73 (dd, 7 = 12.3, 6.4 Hz, 1H), 4.58 (s, 2H), 3.35 (dd, 7

[0230] = 8.3, 5.7 Hz, 1H), 2.86 (dd, J= 13.5, 5.8 Hz, 1H), 2.63 (dd, 7 = 13.4, 8.3 Hz, 1H).

[0231] Preparation of Compound 16

[0232] Reagents and Conditions: (a) BH3-THF, THF, r.t.; (b) 48%wt HBr in water, r.t.; (c) NaHMDS, HMPA, THF, -78°C; (d) TFA, DCM, r.t.; (e) 10% Pd / C, 20% Pd(OH)2 / C, THF, r.t.;

[0233] Preparation of 7-fluoro-6-(hydroxymethyl)-3H-2,1-benzoxaborol-l-ol (16-1)

[0234] To a stirred mixture of 7-fluoro-1-hydroxy-3H-2,1-benzoxaborole-6-carboxylic acid (950 mg, 4.848 mmol, 1 equiv) in THF (10 mF) were added BH3-THF (14.55 mF, 14.544 mmol, 3 equiv, 1 M) dropwise at 0°C. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched with MeOH (5 mF) at room temperature and concentrated under vacuum. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1 % FA), 5% to 40% gradient in 10 min; detector, UV 220 nm] to afford the title product as an off-white solid (910 mg, 97.99%).

[0235] LCMS (ESI): mass calcd. for C8H8BFO3, 182.06; m / z found, 198.90 [M+18-H]-.

[0236] Preparation of (2S)-2-amino-3-(7-fluoro-1-hydroxy-3H-2,1-benzoxaborol-6-yl) propanoic acid (16)

[0237] Starting with the intermediate 16-1 and using essentially the synthetic procedures described for the synthesis Compound 3, steps h-k, the title compound was obtained.

[0238] LCMS (ESI): mass calcd. for C10H11BFNO4, 239.08; m / z found, 240.10 [M+H]+.1H NMR (400 MHz, Deuterium Oxide): δ 7.32 (t, J = 7.5 Hz, 1H), 7.08 (d, J = 7.7 Hz, 1H), 4.85

[0239] (s, 2H), 4.26 (dd, J = 7.3, 6.1 Hz, 1H), 3.30 (dd, J = 14.7, 6.1 Hz, 1H), 3.17 (dd, J = 14.7, 7.3 Hz,

[0240] 1H).

[0241] Preparation of Compound 17 aReagents and Conditions: (a) MeMgBr (3M in 2-MeTHF), THF, rt; (b) Zn, I2, Pd2(dba)3, S-phos, DMF, 45 °C; (c) Xphos Pd G2, Xphos, KOAc, EtOH, 80 °C; (d) LiOH.H2O, THF, H2O, rt; (e) HCl(4 M in dioxane), dioxane, rt.

[0242] Preparation of 2-(4-bromo-2-chlorophenyl)propan-2-ol (17-1).

[0243] To a stirred solution of methyl 4-bromo-2-chlorobenzoate (4.4 g, 17.64 mmol, 1 equiv) in THF (80 mL) was added MeMgBr (3M in 2-MeTHF) (17.64 mL, 52.91 mmol, 3 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at room temperature overnight. The reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to give the title product as a colorless oil (4.32 g, 98.17%). LCMS (ESI): mass calcd. for C9H10BrClO, 248.0; m / z found, 231.0 [M+H-H2O]+. 1H NMR (400 MHz, Chloroform-d) 57.58 (dd, 7 = 8.5, 0.9 Hz, 1H), 7.52 (dd, 7= 2.2, 0.9 Hz, 1H),

[0244] 7.38 (ddd, J = 8.6, 2.1, 0.9 Hz, 1H), 2.25 (s, 1H), 1.71 (d, 7 = 1.0 Hz, 6H). Preparation of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-chloro-4-(2-hydroxypropan -2-yl)phenyl]propanoate (17-2).

[0245] A mixture of Zn (4.53 g, 69.25 mmol, 4 equiv) and I2 (0.44 g, 1.73 mmol, 0.1 equiv) in DMF (80 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (11.40 g, 34.63 mmol, 2 equiv) in DMF (80 mL) and I2(0.44 g, 1.73 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for additional 30 min. To the above mixture was added a solution of 2-(4-bromo-2-chlorophenyl)propan-2-ol (4.32 g, 17.31 mmol, 1 equiv) in DMF (80 mL), Pd2(dba)3(1.59 g, 1.73 mmol, 0.1 equiv) and S- phos (1.07 g, 2.60 mmol, 0.15 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 45 °C overnight. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (50 mL) at room temperature. The resulting mixture was filtered, and the filter cake was washed with EtOAc (2 x 10 mL). The filtrate was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with water (4 x 100 mL), brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18; mobile phase, MeCN in Water (10mmol / L NH4HCO3), 50% to 60% gradient in 5 min; detector, UV 220 nm] to give the title product as a light yellow oil (5.48 g, 85.12%). LCMS (ESI): mass calcd. for C18H26ClNO5, 371.1; m / z found, 370.2 [M-H]-.

[0246] Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3,3-dimethyl-1,3-di hydrobenzo[c][1,2]oxaborol-6-yl)propanoate (17-3).

[0247] To a stirred solution of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[3-chloro-4-(2- hydroxypropan-2-yl)phenyl]propanoate (2 g, 5.38 mmol, 1 equiv) and tetrahydroxydiborane (1.45 g, 16.13 mmol, 3 equiv) in EtOH (40 mL) were added KO Ac (1.58 g, 16.13 mmol, 3 equiv), XPhos Pd G2 (846.36 mg, 1.08 mmol, 0.2 equiv) and X-phos (256.40 mg, 0.54 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 80 °C for 1 h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 3 mL). The filtrate was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the crude product as a yellow oil (2.67 g). The crude product was used in the next step directly without further purification. LCMS (ESI): mass calcd. for C18H26BNO6, 363.2; m / z found, 264.3 [M+H-Boc]+

[0248] Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3,3-dimethyl-1,3- dihydrobenzo[c][1,2]oxaborol-6-yl)propanoate (17-4).

[0249] To a stirred mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3, 3-dimethyl- 1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)propanoate (1 g, 2.75 mmol, 1 equiv) in THF (20 mL) / H2O (10 mL) was added LiOH.H2O (231.04 mg, 5.51 mmol, 2 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (2 x 100 mL). The aqueous layer was acidified to ‘pH 5’ with IN HCl (aq.) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (960 mg) was purified by HP-flash [with the following conditions: column, C18; mobile phase, MeCN in Water ( 10mmol / L NH4HCO3), 50% to 60% gradient in 5 min; detector, UV 220 nm] to give the title product as a white solid (152.7 mg, 15.88%). LCMS (ESI): mass calcd. for C17H24BNO6, 349.2; m / z found, 348.2 [M-H]-.

[0250] Preparation of (S)-2-amino-3-(1-hydroxy-3,3-dimethyl- 1,3-dihydrobenzo[c] [1,2]oxaborol-6- yl)propanoic acid (Example 17).

[0251] To a stirred mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1 -hydroxy-3, 3-dimethyl- 1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)propanoate (152.7 mg, 0.44 mmol, 1 equiv) in dioxane (2.5 mL) was added 4M HCl (in 1 ,4-dioxane) (2.5 mL) at room temperature. The resulting mixture was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (140 mg) was purified by Prep-HPLC [with the following conditions (Column: XBridge Prep Phenyl OBD Column 19*250 mm, 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 2% B to 12% B in 10 min; Wave Length: 254nm / 220nm; RT1 (min): 8.2)] to give the title product as a white solid. (82.3 mg, 75.56%). LCMS (ESI): mass calcd. for CI2HI6BNO4, 249.1; m / z found, 250.2 [M+H]+.1H NMR (400 MH z, Deuterium Oxide) δ 7.51 (s, 1H), 7.37 (q, J = 7.9 Hz, 2H), 4.06 - 3.73 (m, 1H), 3.17 (ddd, J = 59.8, 14.7, 6.6 Hz, 2H), 1.45 (s, 6H).

[0252] Preparation of Compound 18 aReagents and Conditions: (a) MeMgBr, THE, r.t.; (b) B2(OH)4, X-phos, X-phos Pd G2, EtOH, 70 °C; (c) n-BuONO, CuBr, MeCN, 65 °C; (d) Zn, I2, Pd2(dba)3, S-phos, DMF, 40 °C; (e) LiOH H2O, THE, H2O, r.t.; (f) 1,4-dioxane, 4M HCl in dioxane, r.t.

[0253] Preparation of 2-(2-amino-6-bromophenyl)propan-2-ol (18-1).

[0254] To a stirred solution of methyl 2-amino-6-bromobenzoate (2 g, 8.637 mmol, 1 equiv) in tetrahydrofuran (40 mL) was added methylmagnesium bromide, 3 M solution in diethyl ether (14.5 mL, 43.47 mmol, 5 equiv) dropwise under nitrogen atmosphere at 0 °C. The resulting mixture was stirred under nitrogen atmosphere at room temperature for overnight. The reaction was quenched by the addition of water / ice (20 mL) at 0 °C and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 220 nm] to afford the tithe product as a yellow oil (1.6 g, 78.23% yield, 978% purity). LCMS (ESI): mass calcd. for C9H12BrNO, 229.0; m / z found, 230.0 [M+H]+. Preparation of 4-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (18-2).

[0255] A mixture of 2-(2-amino-6-bromophenyl)propan-2-ol (1.4 g, 6.08 mmol, 1 equiv), tetrahydroxydiborane (1.64 g, 18.3 mmol, 3 equiv), Xphos (290 mg, 0.61 mmol, 0.1 equiv), Xphos Pd G2 (480 mg, 0.61 mmol, 0.1 equiv) and AcOK (1.79 g, 18.3 mmol, 3 equiv) in EtOH (28 mL) was stirred under nitrogen atmosphere at 70 °C for 3 h. The resulting mixture was filtered, and the filter cake was washed with EtOH (30 mL). The filtrate was concentrated under reduced pressure and purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 30% gradient in 10 min; detector, UV 220 nm] to afford the title product as a white solid (322 mg, 28.46% yield, 95.2% purity). LCMS (ESI): mass calcd. for C9H12BNO2, 177.1; m / z found, 178.0 [M+H]+.

[0256] Preparation of 4-bromo-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (18-3).

[0257] To a stirred mixture of 4-amino-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (272 mg, 1.54 mmol, 1 equiv) and CuBr (331 mg, 2.31 mmol, 1.5 equiv) in ACN (6 mL) was added tertbutylnitrite (238 mg, 2.31 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred under nitrogen atmosphere at 65 °C for 3 h. After cooling down to room temperature, the reaction was quenched with water / ice at 0 °C and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (2 x 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 5% to 40% gradient in 10 min; detector, UV 220 nm] to afford the title product as a brown oil (160 mg, 43.22% yield, 97.3% purity). LCMS (ESI): mass calcd. for C9H10BBrO2, 240.0; m / z found, 239.00 [M-H]-.

[0258] Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3,3-dimethyl-1,3 dihydrobenzo[c] [1,2]oxaborol-4-yl)propanoate (18-4).

[0259] A mixture of Zn (119.4 mg, 1.83 mmol, 4 equiv) and Iodine (11.6 mg, 0.05 mmol, 0.1 equiv) in DMF (2 mL) was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3- iodopropanoate (300 g, 0.91 mmol, 2 equiv) and Iodine (11.6 mg, 0.05 mmol, 0.1 equiv) in DMF (2 mL) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at room temperature for additional 30 min. To the above mixture was added a solution of 4-bromo-3,3- dimethylbenzo[c][1,2]oxaborol-1(3H)-ol (110 mg, 0.46 mmol, 1 equiv) in DMF (2 mL), Pd2(dba)3(41.8 mg, 0.05 mmol, 0.1 equiv) and S-phos (18.7 mg, 0.05 mmol, 0.1 equiv) at room temperature. The resulting mixture was stirred under nitrogen atmosphere at 40 °C overnight. The reaction was quenched with Water at room temperature and extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (1 x 15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 0% to 50% gradient in 10 min; detector, UV 220 nm] to afford the title product as a light yellow solid (90 mg, 54.26% yield, 99.5% purity). LCMS (ESI): mass calcd. for C18H26BNO6, 363.2; m / z found, 362.3 [M-H]-.

[0260] Preparation ooff (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3,3-dimethyl-1,3- dihydrobenzo[c][1,2]oxaborol-4-yl)propanoic acid (18-5).

[0261] A mixture of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3,3-dimethyl-1,3 dihydrobenzo[c][1,2]oxaborol-4-yl)propanoate (72 mg, 0.2 mmol, 1 equiv) and LiOH·H2O (25.0 mg, 0.6 mmol, 3 equiv) in THF (1.6 mL) and H2O (0.4 mL) was stirred under nitrogen atmosphere at room temperature for 2 h. The mixture was acidified to “pH” 6 with IM HCl (aq.) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title product as a yellow solid (62 mg, crude). LCMS (ESI): mass calcd. for C17H24BNO6, 349.2; m / z found, 348.10 [M-H]-.

[0262] Preparation of (S)-2-amino-3-(1-hydroxy-3,3-dimethyl- 1,3-dihydrobenzo[c] [1,2]oxaborol-4- yl)propanoic acid (Example 18).

[0263] A mixture of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-3,3-dimethyl-1,3- dihydrobenzo[c][1,2]oxaborol-4-yl)propanoic acid (50 mg, 0.14 mmol, 1 equiv) in 1,4-dioxane (0.5 mL) and 4 M HCl in 1,4-dioxane (0.5 mL) was stirred under nitrogen atmosphere at room temperature for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by re versed-phase flash chromatography with [the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 50% gradient in 30 min; detector, UV 220 nm.] to afford the title product as a white solid (15.3 mg, 37.42% yield, 99.2% purity). LCMS (ESI): mass calcd. for C12H16BNO4, 249.1; m / z found, 250.1 [M+H]+.1H NMR (400 MHz, Deuterium Oxide) δ 7.59 (dd, J = 6.5, 1.8 Hz, 1H), 7.43 - 7.30 (m, 2H), 3.95 (dd, J = 8.5, 6.8 Hz, 1H), 3.37 (dd, 7 = 15.0, 6.8 Hz, 1H), 3.12 (dd, 7 = 15.0, 8.6 Hz, 1H), 1.56 (d, 7= 1.9 Hz, 6H).

[0264] Preparation of Compound 19 aReagents and Conditions: (a) CH(OMe)3, conc.H2SO4, MeOH, 65°C,1h; (b) nBuLi, B(OEt)3, Et2O, 70 °C, 2h; (c)N2H4-H2O, EtOH, 60 °C, overnight; (d) Zn, I2, Pd2(dba)3, S-Phos, DMF, rt, 2 h; (e) LiOH-H2O, THE, H2O, rt, 2h; (f) 4M HCl, dioxane, rt, 2h.

[0265] Preparation of 1,3-dibromo-2-(dimethoxymethyl)benzene (19-1).

[0266] To a stirred solution of 2,6-dibromobenzaldehyde (10 g, 37.89 mmol, 1 equiv) in MeOH (100 mL) were added trimethyl orthoformate (4.83 g, 45.47 mmol, 1.20 equiv) and a drop of cone. H2SO4. The resulting mixture was stirred under nitrogen atmosphere at 65 °C for 1 h. The mixture was basified to ‘pH 7’ with CH3ONa. The resulting mixture was concentrated under reduced pressure. The residue was purified [by silica gel column chromatography, eluted with PE / EA (9:1)] to afford to give the title product as a white solid (11.5 g, 97.91%). LCMS (ESI): mass calcd. for C9H10Br2C2, 307.9; no MS signal detected on LCMS. Preparation of methyl 3-bromo-2-formylphenylboronic acid (19-2).

[0267] To a stirred solution of 1,3-dibromo-2-(dimethoxymethyl)benzene (1 g, 3.23 mmol, 1 equiv) in Et2O (20 mL) was added n-BuLi (0.21 g, 3.23 mmol, 1 equiv, 2.5 M in hexane) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred under nitrogen atmosphere at -78 °C for 30 min. To the above mixture was added trimethoxymethane (0.38 g, 3.55 mmol, 1.1 equiv) at -78 °C dropwise over 5 min. The resulting mixture was stirred at -78 °C for additional 30 min. 2M HCl(aq.) was added after 30 min and the resulting mixture was warmed to to -50 °C for 2 h, followed by stirring under nitrogen atmosphere at room temperature for 2 h. After cone, under reduced pressure, the residue was washed with Et2O (2 x 10 mL) to give the title product as a white solid (680 mg, 92.11%). LCMS (ESI): mass calcd. for C7H6BBrO3, 228.0; m / z found, 229.0 [M+H]+.

[0268] Preparation of 5-bromobenzo [d] [1,2,3]d iazaborinin-1(2H)-ol (19-3).

[0269] To a stirred solution of 3-bromo-2-formylphenylboronic acid (1.5 g, 6.56 mmol, 1 equiv) in ethyl alcohol (20 mL) was added N2H4-H2O (0.61 g, 19.67 mmol, 3 equiv). The resulting mixture was stirred under nitrogen atmosphere at 70 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 70% gradient in 10 min; detector, UV 254 nm] to give the title product as a light yellow solid (700 mg, 47.49%). LCMS (ESI): mass calcd. forC7H6BBrN2O, 224.0; m / z found, 225.0 [M+H]+.

[0270] Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-1,2- dihydrobenzo[d] [1,2,3]diazaborinin-5-yl)propanoate (19-4).

[0271] To a stirred solution of Zn (1.16 g, 17.79 mmol, 4 equiv) in DMF (5 mL) was added I2 (0.12 g, 0.489 mmol, 0.1 equiv). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 5 min. To the above mixture was added a solution of methyl (2R)-2-[(tert- butoxycarbonyl)amino]-3-iodopropanoate (2.20 g, 6.67 mmol, 1.5 equiv) in DMF (5 mL). The resulting mixture was stirred under nitrogen atmosphere at room temperature for 30 min. Then to the mixture were added Pd2(dba)3(0.41 g, 0.45 mmol, 0.1 equiv), S-Phos (0.27 g, 0.68 mmol, 0.15 equiv) and 5-bromobenzo[d][l,2,3]diazaborinin-l(2H)-ol (1 g, 4.45 mmol, 1 equiv) in DMF (5 mL). The resulting mixture was stirred under nitrogen atmosphere at 50 °C for overnight. The reaction was quenched with water. The resulting mixture was filtered, and the filter cake was washed with EtOAc (1 x 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 20 mF). The combined organic layers were washed with brine (5 x 20 mL), dried over anhydrous Na2SO4, filtrated, and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography [with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 10% to 60% gradient in 10 min; detector, UV 254 nm] to give the title product as a light brown oil (1.5 g, 97.15%). LCMS (ESI): mass calcd. for C16H22BN3O5, 347.2; m / z found, 346.0 [M-H]-.

[0272] Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-1,2- dihydrobenzo[d][1,2,3]diazaborinin-5-yl)propanoic acid (19-5).

[0273] To a stirred solution methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(1-hydroxy-1,2- dihydrobenzo[d][1,2,3]diazaborinin-5-yl)propanoate (850 mg, 2.45 mmol, 1 equiv) in THE (10 mL) and H2O (5 mL) was added LiOH. H2O (32.95 mg, 3.17 mmol, 2 equiv). The resulting mixture was stirred at room temperature for 2 h. The mixture was acidified to ‘pH 5’ with 2 M HCl (aq.). The resulting mixture was extracted with EtOAc (2 x 5 mF). The combined organic layers were washed with brine (1 x 10 mF), dried over anhydrous Na2SO4, filtrated and concentrated under reduced pressure to give the title product as a light yellow oil (490 mg, 92.84%).

[0274] LCMS (ESI): mass calcd. for C15H20BN3O5, 333.2; m / z found, 332.1 [M-H]-. Preparation of (S)-2-amino-3-(1-hydroxy-1,2-dihydrobenzo[d][1,2,3]diazaborinin-5- yl)propanoic acid (Example 19).

[0275] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(1 -hydroxy- 1,2- dihydrobenzo[d][1,2,3]diazaborinin-5-yl)propanoic acid 440 mg, 1.321 mmol, 1 equiv) in DCM (8 mL) was added TMSI (446 mg, 2.232 mmol, 1.69 equiv) at 0°C. The resulting mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC [with the following conditions (Column: XBridge Shield RP18 OBD Column 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: MeOH— HPLC; Flow rate: 60 mL / min; Gradient: isocratic 2% B to 15% B in 10 min; Wave Length: 254nm / 220nm; RTl(min): 8.82)] to give the title product as a white solid (55 mg, 17.51%). LCMS (ESI): mass calcd. forC10H12BN3O3,233.1; m / z found 234.1 [M-H]-.1H NMR (400 MHz, Deuterium Oxide) 5 8.22 (s, 1H), 7.95 (s, 1H), 7.56 (d, 7 = 4.5 Hz, 2H), 3.74 (s, 1H), 3.50 (d, 7 = 14.2 Hz, 1H), 3.29 - 3.16 (m, 1H).

[0276] Example 2. Cell Uptake Assays

[0277] Cell Culture

[0278] 1.1 Thawing Method

[0279] 1.1.1 15 mL of cell culture medium was placed into a T225 flask.

[0280] 1.1.2 The flask was placed in a humidified 37°C, 5% CO2incubator for 15 minutes to allow medium to equilibrate to the proper pH and temperature.

[0281] 1.1.3 The vial was removed from liquid nitrogen and thawed rapidly by placing at 37 °C in a water bath with gentle agitation for 1-2 minutes and then decontaminated by wiping with 70% ethanol before opening in a Class II biological safety cabinet.

[0282] 1.1.4 The vial contents were transferred dropwise into 10 mL of cell culture medium in a sterile 15 mL conical tube.

[0283] 1.1.5 The cells were centrifuged at 1,300 rpm for 5 minutes.

[0284] 1.1.6 The supernatant was aspirated and re-suspended the cells and transferred the cells into T225 flask containing cell culture medium. 1.2 Propagation Method 1.2.1 Culture medium were renewed every 2-3 days. 1.2.2 Keep the flask in a humidified 37°C, 5% CO2incubator Assay Procedures 2.1 Cell Seeding Cells were harvested and diluted in culture medium to the designated concentration. Then the cells were cultured in T25 flasks, one T25 flask for one sample. 2.2 Formulation of test compounds 2.2.1 L-Boronophenylalanine (L-BPA, 4-boron-L-phenylalanine, Purity: 95%, Chemical formula: C9H12BNO4, MW: 209.01, CAS: 76410-58-7) and fructose were dissolved in PBS at a molar ratio of 1:5, and then a 1.27 M ratio of 1 N NaOH is added. The mixture was stirred until L-BPA is completely dissolved, and the pH value was titrated to 7.2-7.4 with 1 N HCl. 2.2.2 For test compounds other than BPA, stock solutions were prepared of each compound in DMSO or fructose formulation at a concentration of 20 mM (such that final % DMSO in the cellular assay medium= 0.5%) 2.3 Compound treatment 2.3.1 The cells were seeded overnight (12-18 hours) to allow the cells to adhere well. 2.3.2 The stock solution of each compound was added to each T25 flask such that the final concentration for each compound is 100 uM (0.1 mM). 2.3.3 The flasks were placed in a 37 , 5% CO2 incubator for 1 hour, 4 hours and 24 hours. 2.3.4 After treatment for 1 hour, 4 hour, and 24 hours, the cells were collected by using 0.25% Trypsin with 0.53 mM EDTA. 2.3.5 Centrifuged at 1,300 rpm for 5 min to collect cell pellets. Results The compounds disclosed herein were selectively taken up by the representative cancer cell lines SAS (human head & neck cancer), B16F10 (mouse melanoma), and U87-MG (human glioblastoma) relative to a representative normal human cell line (NIH-3T3). Cell uptake of Compound 1 and with L-BPA as comparator Cell uptake of Compound 2-iso2 and with L-BPA as comparator Cell uptake of Compound 3 and with L-BPA as comparator Cell uptake of Compound 5 and with L-BPA as comparator Cell uptake of Compound 6 and with L-BPA as comparator Cell uptake of Compound 7 and with L-BPA as comparator Cell uptake of Compound 8 and with L-BPA as comparator Cell uptake of Compound 9 and with L-BPA as comparator Cell uptake of Compound 11 and with L-BPA as comparator Cell uptake of Compound 17 and with L-BPA as comparator Cell uptake of Compound 18 and with L-BPA as comparator Example 3. Cell Uptake Assays of Compound A (S)-2-amino-3-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)propanoic acid (Comparator Compound A) was tested in cancer and normal cell lines. Cancer cell uptake was similar to that observed with L-BPA and inferior to uptake of compounds 1, 2-iso2, 3, 5, 6, 7, 8, 9, 17 and 18. Cell uptake of Compound A and with L-BPA as comparator INCORPORATION BY REFERENCE All of the U.S. patents and U.S. and PCT patent application publications cited herein are hereby incorporated by reference. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:

1. A compound of Formula (I):wherein A1is selected from –O– and –NH–; A2is selected from –C(O)–, –C(R5)(R6)–, and N; A3is a single bond, –C(R7)(R8)–, or –C(H)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4 is –(CR'R'')nC(H)(NH2)CO2H; R5, R6, R7, and R8are each independently selected from –H and alkyl; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; is a pi bond or absent; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof; provided that if is2 3a pi bond, then A is N and A is –C(H)–; if A1is O; A2is CH2; A3is a single bond; and R3is –CH2C(H)(NH2)CO2H; then at least one of R1, R2, and R4is not H; and if A1is O; A2is CH2; A3is a single bond; and R1is -CH2C(H)(NH2)CO2H; then at least one of R2, R3, and R4is not H.

2. The compound of claim 1 having the structure of Formula (IA):,wherein A1is selected from –O– and –NH–; A2is selected from –C(O)– and –C(R5)(R6)–; A3is a single bond or –C(R7)(R8)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R5, R6, R7, and R8are each independently selected from –H and alkyl; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof; provided that if A1is O; A2is CH2; A3is a single bond; and R3is –CH2C(H)(NH2)CO2H; then at least one of R1, R2, and R4is not H; and if A1is O; A2is CH2; A3is a single bond; and R1is -CH2C(H)(NH2)CO2H; then at least one of R2, R3, and R4is not H.

3. The compound of claim 2, wherein R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4 is –(CH2)nC(H)(NH2)CO2H.

4. The compound of claim 3, wherein R1, R2, R3, and R4are each independently selected from –H, halogen, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CH2)nC(H)(NH2)CO2H.

5. The compound of claim 2 or 3, wherein halogen is –F.

6. The compound of claim 2, wherein R1is not –(CH2)nC(H)(NH2)CO2H.

7. The compound of any one of claims 2-6, wherein A1is selected from –O– and –NH–; A2is selected from –C(O)– and –C(R5)(R6)–; and A3is a single bond.

8. The compound of claim 7, wherein n is 1.

9. The compound of claim 8 having the structure:

10. The compound of claim 9 having the structure selected from:, and; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

11. The compound of claim 10 having the structure selected from:and, wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

12. The compound of claim 10 having the structure selected from:, and; wherein R1, R3, and R4 are not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

13. The compound of claim 10 having the structure selected from:, and; wherein R1, R2, and R4are not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

14. The compound of claim 10 having the structure selected from: , and; wherein R1, R2, and R3are not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

15. The compound of any one of claims 9-14 having the structure selected from:, and, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 8 having the structure:

17. The compound of claim 16 having the structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

18. The compound of claim 17 having the structure selected from:; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

19. The compound of claim 8 having the structure:.

20. The compound of claim 19 having the structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

21. The compound of claim 20 having the structure:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

22. The compound of any one of claims 16-21 having the structure selected from:, , and, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 7, wherein n is 0.

24. The compound of claim 23 having the structure:

25. The compound of claim 24 having the structure selected from:, , ; wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

26. The compound of claim 24 or 25 having structure selected from:, or a pharmaceutically acceptable salt thereof.

27. The compound of any one of claims 2-6, wherein A1 is selected from –O– and –NH–; A2is selected from –C(O)– and –C(R5)(R6)–; and A3is –C(R7)(R8)–.

28. The compound of claim 27, wherein n is 1.

29. The compound of claim 28 having the structure:

30. The compound of claim 29 having structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

31. The compound of claim 29 or 30 having the structure:, or a pharmaceutically acceptable salt thereof.

32. The compound of claim 28 having the structure:

33. The compound of claim 32 having the structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

34. The compound of claim 33 having the structure:; wherein R1is not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

35. The compound of claim 33 or 34 having the structure selected from:, , . And; or a pharmaceutically acceptable salt thereof.

36. The compound of claim 27 having the structure:

37. The compound of claim 36 having the structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

38. The compound of claim 37 having the structure selected from:wherein R1is not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

39. The compound of claim 37 ro 38 having the structure selected from:, , ,and, or a pharmaceutically acceptable salt thereof.

40. The compound of claim 8, wherein R5and R6are each alkyl; or one of R5and R6is alkyl and the other of R5and R6is –H.

41. The compound of claim 40 having the structure selected from:

42. The compound of claim 41 having the structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

43. The compound of claim 41 or 42 having the structure selected from:, or a pharmaceutically acceptable salt thereof.

44. The compound of claim 41 or 42 having the structure:, or a pharmaceutically acceptable salt thereof.

45. The compound of claim 9 having the structure selected from:wherein one of R' and R'' is –H and the other of R' and R'' is halogen or alkyl; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

46. The compound of claim 45 having structure:wherein R1 is not –H; * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

47. The compound of claim 45 or 46 having the structure selected from:, and, or a pharmaceutically acceptable salt thereof.

48. The compound of claim 1 having the structure of Formula (IB):wherein A1is–NH–; A2is N; A3is –C(H)–; R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, alkyl, alkoxy, and –(CR'R'')nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CR'R'')nC(H)(NH2)CO2H; R' and R'' are each independently selected from –H, halogen, and alkyl; n is 0 or 1; and the compound is racemic, enriched in one enantiomer, or a single enantiomer; or a pharmaceutically acceptable salt thereof.

49. The compound of claim 48, wherein R1, R2, R3, and R4are each independently selected from –H, halogen, hydroxy, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CH2)nC(H)(NH2)CO2H.

50. The compound of claim 48, wherein R1, R2, R3, and R4are each independently selected from –H, halogen, and –(CH2)nC(H)(NH2)CO2H, provided that one and only one of R1, R2, R3, and R4is –(CH2)nC(H)(NH2)CO2H.

51. The compound of claim 49 or 50, wherein halogen is –F.

52. The compound of any one of claims 48-51 having the structure selected from:wherein * indicates a chiral carbon with an absolute configuration of (S) or (R); and the compound is not racemic.

53. The compound of claim 52, wherein of R1, R2, R3, and R4are each –H.

54. The compound of claim 53 having the structure:, or a pharmaceutically acceptable salt thereof.

55. The compound of any one of claims 10-14, 17-18, 20-21, 25, 30, 33-34, 37-38, 42, 44-45, and 52, wherein the absolute configuration of the chiral carbon is (S).

56. The compound of any one of claims 10-14, 17-18, 20-21, 25, 30, 33-34, 37-38, 42, 44-45, and 52, wherein the absolute configuration of the chiral carbon is (R).

57. The compound of any one of claims 1-56, wherein the boron atom in the compound is10B.

58. The compound of any one of claims 1-57, wherein n is 1; and R' is –H.

59. The compound of any one of claims 1-58, wherein n is 1; and R'' is –H or halogen.

60. The compound of any one of claims 1-58, wherein n is 1; and R'' is –H or alkyl.

61. The compound of any one of claims 1-58, wherein n is 1; and R'' is halogen.

62. The compound of any one of claims 1-58, wherein n is 1; and R'' is alkyl.

63. The compound of any one of claims 1-58, wherein n is 1; and R'' is –H.

64. A pharmaceutical composition, comprising a compound of any one of claims 1-63; and a pharmaceutical acceptable excipient.

65. The pharmaceutical composition of claim 64, further comprising a saccharide.

66. The pharmaceutical composition of claim 65, wherein the saccharide is fructose.

67. The pharmaceutical composition of any one of claims 64-66, further comprising a polyhydroxy acid.

68. The pharmaceutical composition of claim 67, wherein the polyhydroxy acid is lactobionic acid.

69. The pharmaceutical composition of any one of claims 64-68, further comprising a sugar alcohol.

70. The pharmaceutical composition of claim 69, wherein the sugar alcohol is sorbitol or mannitol.

71. A method of treating cancer, comprising: i) administering to a subject in need thereof a compound of any one of claims 1-63 or a composition of any one of claims 64-70, wherein the compound accumulates in a plurality of cancer cells in the subject; and ii) irradiating the plurality of cancer cells with neutrons.

72. The method of claim 71, wherein the compound selectively or preferentially accumulates in the plurality of cancer cells relative to noncancerous cells in the subject.

73. The method of claim 71 or 72, wherein the irradiation results in conversion of a10B atom in the compound to an -particle and a lithium-7 ion.

74. The method any one of claims 71-73, wherein the compound or the composition is administered intravenously.

75. The method any one of claims 71-74, wherein the cancer is a solid tumor.

76. The method any one of claims 71-74, wherein the cancer is selected from head and neck cancer, glioblastoma, melanoma, and sarcoma.

77. The method any one of claims 71-74, wherein the cancer is unresectable head and neck cancer.

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